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JM Bender, F Li, S Martelly. Sci Transl Med. 2016;8(349):349ra100 Multiple studies have demonstrated that perinatally HIV-exposed but HIV-uninfected (HEU) infants experience greater morbidity and mortality than HIV-unexposed, uninfected infants (HUU). Newborn acquisition of the maternal microbiome provides metabolic and immunologic health benefits. The purpose of this study was to examine the effects of HIV infection on the maternal microbiome and breast milk oligosaccharides and the subsequent impact these may have on the microbiomes of their HEU infants. A total of 50 Haitian mother-infant pairs were studied. All infants were breastfed, and no infants were on antibiotics at the time of the study. A total of 25 HIV-positive mothers and their infants were studied and compared with 25 …

M Muenchhoff, E Adland, O Karimanzira. Sci Transl Med. 2016;8(358):358ra125 HIV-infected, nonprogressing adults appear to control viremia with effective adaptive immune responses. In contrast, the natural primate hosts of simian immunodeficiency viruses (SIVs), such as sooty mangabeys, remain disease-free despite ongoing viral replication. The purpose of this study was to examine the immunologic features and the degree of immune activation in nonprogressing, HIV-infected children (pediatric nonprogressors [PNPs]). 170 HIV-infected children >5 years of age who met the following criteria were studied: antiretroviral (ART) naive, maintaining normal-for-age CD4+ T-cell counts, and clinically nonprogressing. At the time of enrollment, ART was limited to patients whose CD4+ T-cells declined to a specified threshold that the …

D Persaud, H Gay, C Ziemniak. N Engl J Med. 2013;369(19):1828–1835 Until very recently, the only patient “cured” of HIV was the “Berlin patient,” an adult male treated for HIV-associated acute myeloid leukemia with stem cell transplantation from a donor who was intrinsically resistant to HIV. The donor carried homozygous mutations (delta32) in the chemokine receptor 5 gene, which is an essential co-receptor for HIV entry into most target cells. The present study reports on an infant who also may be cured with early, highly active antiretroviral therapy (ART) after documented perinatal infection. A 35-week gestational age infant was born by normal vaginal delivery to an HIV-infected woman who received no prenatal care and who was not taking ART. ART was initiated in the infant …

Y Fukazawa, R Lum, AA Okoye. Nat Med. 2015;21:132–140 A small percentage of HIV-infected patients (elite controllers, EC) appear to be capable of controlling HIV replication, and this is most likely mediated by CD8+ cytotoxic T cells. T follicular helper cells (TFH) are antigen-specific CD3+ CD4+ “helper” T cells that are localized to B-cell follicles of peripheral lymphoid tissue, such as lymph nodes. They are characterized by specific surface antigen expression (PD-1, CXCR5, CD200, ICOS), a specific transcription factor (Bcl6), and specific functions (generation and maturation of antibody responses). In 2012, Perreau et al reported that TFH cells serve as the major CD4+ T-cell compartment for …

MR Gardner, LM Kattenhorn, HR Kondur. Nature . 2015;519(7541):87–91 Although thousands of individuals become infected daily with HIV, attempts to create a protective vaccine have been unsuccessful. The identification of broadly neutralizing antibodies (bNAbs) from individuals with long-term HIV infection raised the possibility that such antibodies might be generated. Unfortunately, bNAbs are not particularly broadly neutralizing. This article reports the development of an engineered “immunoadhesin protein” with the potential to function as an effective HIV vaccine. In vitro studies and rhesus macaque monkeys. In vitro studies were conducted to assess the capacity of candidate protein constructs to neutralize HIV isolates, including those resistant to bNAbs. Subsequently, a candidate construct adapted to rhesus macaque monkeys was cloned into an adeno-associated virus (AAV) vector. …

AB Balazs, Y Ouyang, CM Hong. Nat Med. 2014;20(3):296–300 A large majority of new HIV infection results from transmission across mucosal barriers. HIV vaccine clinical trials have failed to illicit protective immunity to infection. Furthermore, pre-exposure and postexposure prophylaxis regimens have had limited success, primarily due to nonadherence to the prescribed regimens. Protection with currently available vaccines to mucosal infections, such as human papilloma virus and influenza virus, correlate with systemic neutralizing antibodies. The purpose of this study was to evaluate a new strategy for prevention of HIV transmission, “vectored immunoprophylaxis,” a specific form of gene transfer therapy in which the gene for a modified broadly neutralizing antibody is directed into …

Objectives. To determine the pharmacokinetic properties, tolerance, safety, and preliminary activity of stavudine in human immunodeficiency virus (HIV)-infected children. Design. Phase I/II, open and dose-ranging (0.125 to 4 mg/kg/day in two divided doses). Patients. Thirty-seven HIV-infected children (median age, 5.5 years; range, 7 months to 15 years) with a median CD4+ lymphocyte count at baseline of 242 cells/µL (range 2 to 2290 cells/µL). Thirty children had symptomatic HIV disease at entry; seven had HIV-related immunosuppression alone. Twenty-nine subjects had a history of prior zidovudine (ZDV) therapy. Results. As compared with adults receiving the same weight-adjusted doses, the children we studied had lower maximum observed stavudine plasma concentrations (CMAX) and area under the plasma concentration versus time curves (AUC), and more rapid stavudine elimination. The absolute oral bioavailability of the drug ranged from 61% to 78%. There was no plasma accumulation of the drug between day 1 and week 12. Week 12 cerebrospinal fluid stavudine concentrations in seven subjects, obtained approximately 2 to 3 hours after oral doses, ranged from 16% to 97% of concomitant plasma concentrations. Stavudine was well-tolerated and there were no dose-related clinical or laboratory adverse events. One subject with baseline neurologic abnormalities experienced a transient episode of apparent pain or discomfort in her fingers, possibly related to stavudine. All other adverse events were attributed to underlying disease. Stavudine activity, measured indirectly by CD4+ lymphocyte count and serum p24 antigen concentration changes, was observed in some subjects. Progression of HIV disease and survival correlated with prior ZDV therapy, HIV disease classification, baseline CD4+ lymphocyte count, and weight growth velocity. Conclusions. Stavudine appears to hold promise for the treatment of HIV infection in children. Its pharmacokinetic properties are consistent and predictable, and it appears to be remarkably well-tolerated and safe. Although our study was not designed to assess the drug's efficacy, preliminary clinical and laboratory evidence of activity was observed.

Objective. Zidovudine and didanosine are both beneficial for the treatment of human immunodeficiency virus (HIV) infection in children. Because disease progression and toxicity often limit their long-term use as single agents, new approaches to using nucleoside analogues are necessary to improve current antiretroviral therapy. Design. We conducted a phase I-II study to evaluate the tolerance, pharmacokinetics, and antiviral activity of the combination of zidovudine and didanosine in children with HIV infection. Sixty-eight children who were either previously untreated or who had manifested hematologic toxicity on full-dose zidovudine were enrolled. Eight dose combinations were studied in the previously untreated children, with doses of zidovudine ranging from 90 to 180 mg/m2 every 6 hours and doses of didanosine ranging from 90 to 180 mg/m2 every 12 hours. Results. Fifty-four previously untreated HIV-infected children were enrolled in this part of the study, of whom 49 remained in the study for a minimum of 24 weeks. For children with previous zidovudine-related hematologic toxicity, three dose levels with zidovudine at 60 mg/m2 every 6 hours orally and didanosine ranging from 90 to 180 mg/m2 every 12 hours orally were used. A total of 14 children were enrolled in this part of the study, and 12 remained on therapy for at least 24 weeks. No evidence of new or enhanced toxicity was observed in either group. After 24 weeks, the median CD4 cell count for all patients increased from 331 to 556 cells/mm3 (P = .01). For the previously untreated group, the median increase in CD4 counts was from 386 to 726 cells/mm3 (P = .003). The median p24 antigen concentration (in those with a detectable level at baseline) decreased from 95 to Conclusions. The combination of zidovudine and didanosine was well-tolerated at doses as high as those used in single agent therapy. Potent in vivo antiviral activity was observed. Combination therapy with nucleoside analogues may be an important approach to optimizing the use of these agents in the treatment of HIV infection.

GD Tomares, G Ferrari, X Shen. Proc Natl Acad Sci U S A. 2013;110(22):9019–9024 A recently completed Phase III vaccine trial demonstrated a 32% estimated efficacy. An earlier analysis suggested that envelope (Env)-specific antibody responses were associated with a lower risk of infection. Of particular interest, anti-HIV Env immunoglobulin A (IgA) antibodies correlated with increased infection risk. The purpose of this study was to evaluate potential mechanisms of …

J Lewis, S Walker, H Castro. J Infect Dis. 2012;205(4):548–556 US guidelines for initiating antiretroviral therapy (ART) for children with HIV infection suggest treatment in all patients younger than 12 months of age and for children older than 12 months of age depending upon immunologic (CD4 count) and virologic (plasma viral load) measures. The guidelines, therefore, assume that it is safe to delay therapy in some older children. However, poorer reconstitution of CD4 count has been demonstrated in pediatric patients who start ART at an older age …

SE Lipshultz, WT Shearer, B Thompson. J Am Coll Cardiol. 2011;57(1):76–85 HIV is known to cause a cardiomyopathy. In addition, the mitochondrial abnormalities reported in children exposed to antiretroviral therapy but not infected with HIV might also be associated abnormal heart function. The purpose of this study was to examine the cardiac effects of perinatal exposure to antiretroviral therapy. This was a prospective multisite cohort study with …

Gulick RM, Lalezari J, Goodrich J, et al. N Engl J Med . 2008;359(14):1429–1441 PURPOSE OF THE STUDY. Although there are now >20 anti-HIV medications, new agents are still needed. HIV drug resistance is highly prevalent and 15% of newly infected patients in the United States have drug-resistant virus. In addition, enhanced safety and tolerability and improved convenience would enhance adherence to antiretroviral regimens. HIV uses 1 of 2 chemokine receptors, in addition to CD4, to gain entry into a cell, chemokine receptor 5 (CCR5) and α-chemokine receptor 4 (CXCR4). HIV that uses CCR5 is the primary type of virus that is transmitted through sexual or perinatal exposure. CCR5 antagonists are a new class of antiretroviral agents. The purpose of this study was to evaluate a CCR5 antagonist, maraviroc, …

Steigbigel RT, Cooper DA, Kumar PN, et al. N Engl J Med . 2008;359(4):339–354 PURPOSE OF THE STUDY. As described above, there are compelling reasons for expanding the anti-HIV armamentarium. Raltegravir is an inhibitor of HIV integrase, an enzyme essential in the cycle of HIV replication. Because it belongs to a novel class of antiretroviral agents, the drug should be effective against HIV that is resistant to other antiretroviral drugs. The purpose of this study was to evaluate the safety and effectiveness of raltegravir in adults with multidrug-resistant virus. STUDY POPULATION. HIV-infected patients ≥16 years of age were eligible if they had plasma HIV RNA levels of >1000 …

Objective. To determine the safety and efficacy of anabolic therapy to prevent or reverse wasting and malnutrition in human immunodeficiency virus (HIV)-infected pediatric patients. The anabolic steroid, oxandrolone, was evaluated because of its safe and effective use in other pediatric conditions. Methods. Nine HIV-positive children who were malnourished or at risk for malnutrition (4 females, 5 males; 4–14 years of age) took oxandrolone for 3 months (.1 mg/kg/day orally). Quantitative HIV ribonucleic acid polymerase chain reaction and CD4+ T-cell levels, complete blood cell count (CBC) and chemistry profile, endocrinologic studies, resting energy expenditure, respiratory quotient, nutritional measures, body composition assessment with quantitative computed tomography, and skinfold body composition measurements were determined before treatment, during treatment (3 months), and for 3 months after treatment. Statistical analyses were completed using the Friedman two-way analysis of variance and Spearman correlation tests. Results. No adverse clinical or laboratory events or changes in Tanner staging or virilization occurred. Quantitative HIV ribonucleic acid polymerase chain reaction and CD4+ T-cell levels did not change significantly. Insulin-like growth factor 1 increased, suggesting an anabolic effect of treatment. The rate of weight gain increased during treatment and was maintained after treatment. Linear growth continued and was maintained throughout treatment, whereas bone age did not increase significantly. Anthropometric assessments indicated an increase in muscle mass and a decrease in fat while patients were on treatment, and a mild decrease of muscle and increased fat posttreatment. Likewise, computed tomography scan results demonstrated similar changes in muscle mass. Resting energy expenditure and respiratory quotient remained stable throughout treatment and follow-up. No significant changes were seen in the quality of life questionnaire. Conclusions. Treatment with oxandrolone for 3 months in HIV-infected children was well-tolerated, safe, and associated with markers of anabolism. The latter effect was maintained partially for 3 months after discontinuation of a 3-month course of therapy. Additional studies are needed to assess the potential benefits and risks of a longer course of therapy or a higher dose of oxandrolone in HIV-infected children.

Mallal S, Phillips E, Carosi G, et al. N Engl J Med. 2008;358(6):568–579 PURPOSE OF THE STUDY. Abacavir is associated with severe and potentially life-threatening hypersensitivity reactions in up to 8% of the white population. In 2002, HLA-B*5701 was noted to be highly associated with this hypersensitivity reaction. The purpose of this study was to evaluate the effectiveness of prospective HLA-B*5701 screening to avoid these reactions. STUDY POPULATION. A total of 1956 HIV-infected patients from 19 countries who had not previously received abacavir were enrolled. METHODS. Individual patients were randomly assigned to undergo prospective HLA-B*5701 screening, with exclusion of previously known HLA-B*5701 positive patients from abacavir treatment, or to undergo a standard approach of abacavir use without screening. All subjects who started abacavir were observed for 6 weeks, the time frame in which a large majority of hypersensitivity reactions occur. The clinical diagnosis of hypersensitivity reaction to abacavir was assessed further by epicutaneous patch testing. RESULTS. The prevalence of HLA-B*5701 was 5.76% (109 of 1956 subjects) of the subjects assigned to receive abacavir. Seventy-two percent were men, 84% were white, and 18% had not received antiretroviral therapy previously. Screening effectively eliminated patch-test–confirmed hypersensitivity. None of the subjects in the prospectively screened group had reactions, compared with 2.7% in the control group. This yielded a negative predictive value of 100% and a positive predictive value of 47.9%. Hypersensitivity reactions to antiretroviral therapy were clinically diagnosed in 93 patients, with a significantly lower incidence in the prospectively screened group (3.4%) than in the control group (7.8%) (P < .001). CONCLUSIONS. HLA-B*5701 screening dramatically reduced the risk of immunologically confirmed hypersensitivity to abacavir. This pharmacogenetic test is useful for reducing the incidence of immunologically mediated hypersensitivity reactions to abacavir. REVIEWER COMMENTS. This expansive study demonstrated the clinical usefulness of pharmacogenomics testing for immunologically mediated hypersensitivity to a particular drug. This is the first such demonstration for reactions to antiretroviral agents. A major limitation in the use of abacavir has been the concern for a severe hypersensitivity reaction. The availability of this inexpensive test (approximately $80 at our institution) substantially reduces that potential and allows antiretroviral therapy selection to be based on the drug's merit as an effective antiretroviral agent. A unique feature of hypersensitivity to this particular drug is that it is a true T-cell–mediated reaction. Patch testing has been used for many decades to identify offending contact hypersensitivity allergens (eg, nickel). The search for additional biomarkers that would reflect a potential for adverse reactions to other drugs is ongoing. This type of study leads the way in demonstrating clinical effectiveness of such an approach

Correa R, Harari A, Vallelian F, et al. AIDS. 2007;21(1):23–30 PURPOSE OF THE STUDY. HIV-specific CD4+ T cells seem to play a critical role in antiretroviral immunity and particularly in maintaining cytotoxic T-cell responses. The objective of this study was to evaluate the function of HIV-specific T cells in antiviral treated, HIV-infected children. STUDY POPULATION. The researchers evaluated 23 HIV-infected children who were treated with antiretroviral therapy for a mean of 7 years. METHODS. Flow-cytometric analysis was used to measure the ability of HIV-specific T cells to secrete interleukin 2 (IL-2) and interferon γ (IFN-γ) after stimulation of patient cells with p55 gag protein. RESULTS. Three patterns of intracellular cytokine generation were identified: in 10 subjects, antigen-specific cytokine production was characterized by IL-2 production, 8 subjects’ CD4+ T cells expressed IL-2 and IFN-γ, and 5 subjects’ T cells expressed IFN-γ alone. These 3 groups were then analyzed for factors that might explain the different patterns. The patterns correlated with viral load at the time of functional analysis and over the previous 2 years. The group with dominant IFN-γ responses had high viremia levels, a pattern similar to that observed in patients with uncontrolled viral replication. Patients with combined IL-2 and IFN-γ production had relatively lower viral loads but had experienced viral “blips” over the 2 years before analysis. This pattern was similar to adults who were long-term nonprogressors or those whose conditions continued to progress despite antiretroviral therapy. The subjects with a dominant IL-2 response had very low levels of viremia and had not experienced viral “blips” over the previous 2 years. This pattern was similar to that generally observed in individuals who have cleared the infecting agent. It is important to note that this pattern has not been observed in HIV-infected adults. CONCLUSIONS. Children with HIV have a higher frequency of HIV-specific CD4+ T cells compared with adults, and their recovery of an IL-2–secreting T-cell pattern indicates a greater capacity for immune restoration in children than adults. REVIEWER COMMENTS. This elegant study provides a biological rationale for the clinical observation that young children started on antiretroviral therapy have the capacity for remarkable reconstitution of immune functions relative to those reported in adults and older children who have been infected for prolonged periods before antiretroviral therapy. Perhaps it is unfair to compare these results with findings in adults that included patients who were infected for many years before their initiation of therapy. A more appropriate comparative adult group would be those treated within 6 months of their diagnosis. Most importantly, this study demonstrates that children are “different” and that treatment early in infection allows excellent immune reconstitution if viral replication is completely controlled.

Chaparro AI, Mitchell CD, Abitbol CL, et al. J Pediatr. 2008;152(6):844–849 PURPOSE OF THE STUDY. Proteinuria is a common feature of HIV infection and a potential complication of therapy in adult patients. This study was performed to determine the prevalence of proteinuria in a group of children infected with HIV and to assess this process over time and the impact of antiretroviral therapy on it. STUDY POPULATION. HIV-infected children (N = 286) were studied from 1998 through 2006. METHODS. Proteinuria was determined by random urine protein/creatinine ratios, with “normal” defined as 1.0. RESULTS. A total of 94 (33%) of the children had proteinuria at baseline. Of these, 32 had urine protein range ratios of ≥1.0. Clinically, the mortality rate was higher in those patients with proteinuria. It is important to note that 55 of the 94 patients with baseline proteinuria showed a good response to antiretroviral therapy, as indicated by a decrease in HIV viral load and a substantial reduction in the number of subjects who had proteinuria. CONCLUSIONS. Control of HIV viremia with antiretroviral therapy reduces progression of HIV-associated proteinuria and improves the survival rate of infected children. REVIEWER COMMENTS. Proteinuria is a common feature of HIV infection in children. Two features of this patient population may affect the generalizability of the study findings: 85% of the patients were African American or African Caribbean, and the number of individuals with complicating hepatitis B or C was not indicated. Renal disease is more prevalent in HIV-infected black people than white people, particularly with respect to HIV-associated nephropathy. Chronic viral hepatitis may also cause secondary renal disease, likely secondary to an immunocomplex-associated inflammatory process. Regardless of these caveats, the authors’ conclusion is very much warranted: “surveillance of quantitative proteinuria with imaging and chemical indicators of renal dysfunction is very much warranted” for children with HIV infection.

Trautmann L, Janbazian L, Chomont N, et al. Nat Med. 2006;12:1198–1202 PURPOSE OF THE STUDIES. Recent evidence from a mouse model of chronic viral infection suggests a crucial role for the programmed death 1 (PD-1)/programmed death 1 ligand (PD-L1) signaling pathway in downregulating the functions of virus-specific CD8+ T cells. PD-1 is an inhibiting receptor that negatively regulates activated T cells, and it is markedly upregulated on the surface of “exhausted” virus-specific CD8+ T cells in mice. HIV similarly induces a virus-specific impairment of T-cell functions. The purpose of these 2 studies was to investigate the expression of PD-1 on HIV-specific T cell in patients infected with the virus. STUDY POPULATION AND METHODS. Both studies evaluated subjects with HIV and healthy controls and compared PD-1 expression in these individuals on virus-specific T cells. A panel of MHC class I tetramers were used to identify HIV-specific CD8+ T cells. PD-1 expression was then measured on tetramer-positive cells. PD-1 expression was also analyzed on cytomegalovirus-specific, Epstein-Barr virus–specific, and vaccinia virus–specific CD8+ T cells from HIV-negative controls. RESULTS. The findings in these studies were remarkably similar. PD-1 was significantly upregulated on HIV-specific T cells, and expression correlated with impaired HIV-specific CD8+ T-cell function as well as predictors of disease progression: HIV viral load, a reduced capacity for cytokine production, and decreased proliferation of HIV-specific CD8+ T cells. Cytomegalovirus-specific CD8+ T cells from the same donors did not upregulate PD-1 and seemed to maintain functional integrity. Blockade of the PD-1/PD-1L pathway result reversed immune dysfunction. CONCLUSIONS. The PD-1/PD-1L pathway is associated with significant HIV-specific T-cell exhaustion. The accumulation of HIV-specific dysfunctional T cells in an infected host may prevent the renewal of a functionally competent HIV-specific CD8+ T-cell response. REVIEWER COMMENTS. HIV has proven remarkably adept at inhibiting the very system that evolved to control it. Expression of a negative regulator of activated T cells, PD-1, is markedly increased on HIV-specific CD8+ T cells when HIV engages the T-cell receptor. Such T cells have been termed “exhausted” because they fail to respond as fully activated effector cytotoxic T cells. Surprisingly, blockade of PD-1 engagement with its ligand results in a restoration of T-cell function. This observation suggests a target for enhancing the function of exhausted T cells in HIV-infected individuals. However, much has to be learned about the importance of this pathway in the control of normal T-cell activation. T-cell activation seems to be an intrinsic component of HIV pathogenesis; therefore, blocking this activation may be useful. However, it would be potentially dangerous to be unable to turn off an activated immune response to a routine infection.

Alimenti A, Forbes JC, Oberlander TF, et al. Pediatrics. 2006;118(4). Available at: www.pediatrics.org/cgi/content/full/118/4/e1139 PURPOSE OF THE STUDY. The effective treatment of HIV-infected women with antiretroviral agents has dramatically reduced the incidence of HIV infection in their newborn infants. However, an ongoing concern has been the potential adverse effects of the antiretroviral agents themselves on the neurodevelopment of HIV-uninfected children who were exposed to combination HIV medications. The purpose of this study was to investigate the neurodevelopment of HIV-infected children exposed to combination anti-HIV therapy in pregnancy compared with children not exposed to this therapy. STUDY POPULATION. A total of 39 antiretroviral therapy–exposed and 24 control children were assessed. METHODS. This was a prospective, controlled, cross-sectional study. The Bailey Scales of Infant Development and Vineland Adaptive Behavior scales were performed at 18 to 36 months of age. Control children were born to HIV-uninfected women with similar anticipated social and economic backgrounds. Results were compared by using analysis of covariance and χ2 analysis. RESULTS. All scores were lower for children who were exposed prenatally to antiretroviral therapy. However, when maternal substance use during pregnancy was controlled for, there were no significant differences between the groups in any of the domains assessed. Children in both groups who were exposed to maternal substance use scored significantly lower in most domains than children who were not exposed. CONCLUSIONS. HIV and antiretroviral therapy–exposed HIV-uninfected children had lower development and adaptive behavior scores compared with children who were not exposed to HIV or anti-HIV drugs. It is important to note that these differences were not significant when maternal substance use was considered. In this prospective study, exposure to perinatal anti-HIV therapy was not associated with neurodevelopmental abnormalities. REVIEWER COMMENTS. This small study demonstrated that maternal substance use impacted the neurodevelopment of children to a far greater extent than exposure to anti-HIV drugs. In this study, at least, any negative impact of antiretroviral drugs on infant neurodevelopment was masked by the maternal substance use. This is not to say that exposure to combination anti-HIV medications may not have an impact on childhood development. Studies with similar designs to this one, in larger numbers of children for whom maternal substance use is not a confounding factor, will be required to address this issue fully.

Purpose of the Study. An inexpensive, effective regimen to prevent perinatal HIV transmission in the developing world is highly desirable. Nevirapine, a nonnucleoside reverse transcriptase inhibitor, seems to provide such an intervention. However, drug-resistance mutations have been identified in up to 40% of women shortly after they received a single intrapartum nevirapine dose as part of a transmission-prevention strategy. This study was undertaken to reexamine the incidence of drug-resistant HIV-1 after single-dose nevirapine. Study Population. Fifty South African women infected with HIV subtype C. Methods. Sensitive, real-time polymerase chain reaction assays were sequentially performed for nonnucleoside reverse transcriptase inhibitor–resistance mutation, K103N and Y181C. Results. Resistance mutations emerged in 65% of women after a single dose of nevirapine. Conclusions. Single-dose nevirapine as used in the developing world for prevention of perinatal HIV transmission results in the development of resistance mutations in a very high percentage of women who receive this intervention. Reviewer Comments. Although single-dose nevirapine has been successfully implemented as a strategy to prevent perinatal HIV transmission, it is increasingly apparent that the women who are treated with this regimen more often than not develop resistance mutations to nevirapine. The clinical implications are clear: Will nevirapine work for future perinatal interventions for individual women with drug-resistance mutations? Will women with these drug-resistance mutations fail to respond to nevirapine as part of a highly active retroviral therapy intervention when they need treatment for their own HIV disease? In the same issue of The Journal of Infectious Diseases, Flys et al (J Infect Dis. 2005;192:24–29) demonstrated that drug-resistance variants of HIV may persist for >1 year in this situation. In addition, Lee et al (J Infect Dis. 2005;192:1260–1264) showed that women who developed drug-resistant HIV after exposure to single-dose nevirapine shed drug-resistant HIV in their breast milk. This increases the risk of transmission of resistant virus to uninfected infants. Together, these studies demonstrate that single-dose nevirapine, although an effective strategy for reducing maternal-child transmission of HIV, also predisposes treated women to the development of drug-resistant virus as well as the potential for transmitting drug-resistant virus to their infants via breastfeeding.

Purpose of the Study. Tenofovir and didanosine are adenosine analogs commonly used in highly active antiretroviral therapy combinations. Although virologically effective, this combination is theoretically associated with pharmacokinetic interactions and increased risks of pancreatitis and hyperglycemia. The study examined the CD4+ T-cell effects of the use of these 2 drugs as part of a highly active antiretroviral therapy regimen. Methods. Data from 570 individuals were analyzed retrospectively according to the nucleoside analog “backbone” of protease inhibitor–containing regimens: tenofovir + didanosine in 298 subjects, didanosine in 88, tenofovir in 44, and neither didanosine nor tenofovir in 140. Results. Significant CD4+ T-cell declines were noted in patients taking the combination of tenofovir + didanosine relative to all other nucleoside analog combinations including didanosine or tenofovir only. Patients exposed to higher didanosine doses showed a more pronounced CD4+ T-cell decline, and plasma levels of didanosine correlated with the extent of T-cell loss. Conclusions. Although patients receiving tenofovir + didanosine–based combinations generally achieved excellent viral suppression, their CD4+ T cells often paradoxically declined. This effect generally progressed over time. It is hypothesized that the use of these 2 agents together results in a condition that metabolically resembles purine nucleoside phosphorylase deficiency, a rare but well-described primary immunodeficiency syndrome. Reviewer Comments. Tenofovir and didanosine frequently are the only nucleoside analog agents available to patients with drug-resistant virus. This combination with either a nonnucleoside reverse transcriptase inhibitor or a protease inhibitor is often effective in suppressing virus in patients with limited options. However, the paradoxical decline in T-cell numbers is of great concern. Patients on this regimen must be monitored carefully for this potential complication.

Brenchley JM, Schacker TW, Ruff, LE, et al. J Exp Med . 2004;200:749–759 Mechanisms underlying T-cell depletion in HIV infection are not well understood. This depletion has been studied primarily in the peripheral blood and, to some extent, in peripheral lymphoid tissue. However, a large fraction of CD4+ T cells reside in the gastrointestinal tract. The purpose of this study was to identify the effects of HIV infection on activation and depletion of T cells in the peripheral blood, gastrointestinal tract, and lymph nodes. A total of 14 antiretroviral therapy–naive HIV-infected individuals and 7 HIV-uninfected individuals were recruited. …

Vigano A, Saresella M, Trabattoni D, et al. J Pediatr . 2004;145:542–548 Growth hormone (GH) plays a role in thymic function, and decreased hormone secretion has been reported in HIV-infected children. Highly active antiretroviral therapy suppresses HIV replication and results in increases in CD4+ T cells in HIV-infected patients. The aim of this study was to determine if the level of immune reconstitution associated with antiretroviral therapy is influenced by the …

T Vollbrecht, R Stirner, A Tufman. AIDS. 2012;26(12):F31–F37 Myeloid-derived suppressor cells (MDSC) consist of a heterogeneous population of progenitor cells and immature myeloid cells that are potent suppressors of T-cell function in many tumor models. The purpose of this study was to evaluate the possibility that MDSC play a role in HIV-induced immunosuppression. Ninety-seven patients participated in this study: 16 healthy controls; 20 HIV-infected individuals with suppressed viral loads; 49 HIV-infected treatment-naive individuals; 2 individuals with hepatitis C co-infection; 4 HIV-infected individuals failing to respond to treatment; and 8 …

Objective. Despite dramatic reductions in perinatal human immunodeficiency virus (HIV) transmission in the United States, obstacles to perinatal HIV prevention that include lack of prenatal care; failure to test pregnant women for HIV before delivery; and lack of prenatal, intrapartum, or neonatal antiretroviral (ARV) use remain. The objective of this study was to describe trends in perinatal HIV prevention methods, perinatal transmission rates, and the contribution of missed opportunities for perinatal HIV prevention to perinatal HIV infection. Methods. We analyzed data obtained from infant medical records on 4755 HIV-exposed singleton deliveries in 1996–2000, from 6 US sites that participate in the Centers for Disease Control and Prevention’s Pediatric Spectrum of HIV Disease Project. HIV-exposed deliveries refer to deliveries in which the mother was known to have HIV infection during the pregnancy. Results. Of the 4287 women with data on prenatal care, 92% had prenatal care. From 1996 to 2000, among the 3925 women with prenatal care, 92% had an HIV test before delivery; the use of prenatal zidovudine (ZDV) alone decreased from 71% to 9%, and the use of prenatal ZDV with other ARVs increased from 6% to 70%. Complete data on maternal and neonatal ARVs were available for 3284 deliveries. Perinatal HIV transmission was 3% in 1651 deliveries with prenatal ZDV in combination with other ARVs, intrapartum ZDV, and neonatal ZDV; 6% in 1111 deliveries with prenatal, intrapartum, and neonatal ZDV alone; 8% in 152 deliveries with intrapartum and neonatal ZDV alone; 14% of 73 deliveries with neonatal ZDV only started within 24 hours of birth; and 20% in 297 deliveries with no prenatal, intrapartum, and neonatal ARVs. Complete data on prenatal events were available in 328 HIV-infected and 3258 HIV-uninfected infants. A total of 56% of mothers of HIV-infected infants had missed opportunities for perinatal HIV prevention versus 16% of mothers of HIV-uninfected infants. Forty-four percent of the infected infants were born to mothers who had prenatal care, a prenatal HIV diagnosis, and documented prenatal ARV therapy. Seventeen percent of women with reported illicit drug use had no prenatal care versus 3% of women with no reported drug use. In a multivariate analysis, maternal illicit drug use was significantly associated with lack of prenatal care. In a multivariate analysis, year of infant birth and the combination of lack of maternal HIV testing before delivery and lack of prenatal antiretroviral therapies were significantly associated with perinatal HIV transmission. Conclusions. Missed opportunities for perinatal HIV prevention contributed to more than half of the cases of HIV-infected infants. Prenatal care and HIV testing before delivery are major opportunities for perinatal HIV prevention. Illicit drug use was highly associated with lack of prenatal care, and lack of HIV testing before delivery was highly associated with perinatal HIV transmission.

Cohen MH, Olszewski Y, Branson B, et al. AIDS. 2003;17:2121–2124 The US Food and Drug Administration recently approved the OraQuick rapid human immunodeficiency virus-1 (HIV-1) antibody test (OraSure Technologies, Bethlehem, PA). The test is designed for point-of-care testing for HIV. The test is performed with a tiny amount of blood, and results are available within 20 to 30 minutes. Remarkably, this test is as sensitive and specific as the standard enzyme-linked immunosorbent assay for HIV-specific antibodies. The purpose of this study was to evaluate the differences in turnaround times between hospitals where obstetric staff members performed the rapid …

Tesselaar K, Arens R, van Scijndel GMW, et al. Nat Immunol . 2003;4:49–54 During human immunodeficiency virus (HIV) infection, CD4+ T cell levels decline. Studies suggested that this loss is less likely related to direct infection and killing of these cells than to exhaustion of the T cell pool induced by chronic immune activation. The purpose of this study was to determine, in an animal model, whether artificially induced chronic immune activation alone …

KM Knapp, SB Brogly, DG Muenz. Pediatr Infect Dis J. 2012;31(2):164–170 The use of effective, fully suppressive antiretroviral (ARV) therapy during pregnancy dramatically lowers mother-to-child transmission of HIV. Currently, nucleoside reverse transcriptase inhibitors form the foundation of ARV combination therapy for pregnant women; however, these drugs have potential negative consequences for the developing fetus. This study examined the prevalence of congenital anomalies in infants who were exposed in utero to ARV drugs. International Maternal Pediatric Adolescent AIDS Clinical Trials …

Purpose of the Study. Zidovudine (AZT) has been shown to reduce maternal-infant transmission of human immunodeficiency virus (HIV) by two thirds. Combination antiretroviral therapy may improve this transmission rate. The objectives of this study were to assess the safety of the combination of lamivudine (3TC)-AZT therapy for the prevention of maternal-infant HIV transmission. Methods. An open label, nonrandomized trial was conducted at 48 clinical sites in France. Four-hundred forty-five HIV-infected pregnant women were enrolled in the study. The study cohort …

W Ferguson, M Goode, A Walsh, P Gavin, K Butler. Pediatr Infect Dis J. 2011;30(5):408–412 A 6-week course of neonatal antiretroviral prophylaxis has been standard in most developed countries. In the same settings, a 4-week rather than 6-week intervention might reduce toxicity and reduce cost. The study involved a cohort that included all HIV-exposed live births in …

K Allers, G Hutter, J Hofmann. Blood. 2011;117(10):2791–2799 HIV uses CD4+ as its primary receptor and chemokine receptors (CCR5 and CXCR4) as coreceptors. The primary receptor used to transmit HIV between people, including in maternal-child transmission, is CCR5. Approximately 1% of northern Europeans have a homozygous deletion (Δ32) in the CCR5 gene that dramatically increases the resistance to HIV infection in affected people. There has been great speculation as to …

Hutter G, Nowak D, Mossner M, et al. N Engl J Med . 2009;360(7):692–698 PURPOSE OF THE STUDY. HIV infection of a target cell requires the expression of CD4 and a chemokine receptor. Early after HIV transmission, the chemokine coreceptor used most often is chemokine receptor 5 (CCR5). Approximately 1% of Northern European individuals possess homozygosity for a 32-base pair deletion (Δ32) in their CCR5 genes. These individuals are exceptionally resistant to HIV infection with CCR5-expressing HIV. The purpose of this study was to determine whether HIV could …

Pensieroso S, Cagigi A, Palma P, et al. Proc Natl Acad Sci U S A . 2009;106(19):7939–7944 PURPOSE OF THE STUDY. HIV infection induces a progressive decline in immune function that affects not only T-cell but also B-cell activities, including the progressive decline in memory B cells, markedly elevated serum immunoglobulin levels, impaired responsiveness to routine immunizations, and loss of specific antibodies previously generated. Treatment of adults with highly active antiretroviral therapy (HAART) reduces immunoglobulin levels and increases B-cell numbers. However, several studies indicate that the B-cell compartment does not recover completely and patients maintain impaired antibody responses to immunizations. The purpose of this study was to determine whether the timing …

1. Miller KD, 2. Jones E, 3. Yanoski JA, 4. Shankar R, 5. Feuerstein I, 6. Falloon J (1998) Lancet. 351:871–875. [OpenUrl][1][CrossRef][2][PubMed][3][Web of Science][4] #### Purpose of the Studies Protease inhibitors represent a major advance in the treatment of human immunodeficiency virus (HIV) infection, and constitute the cornerstone of highly active antiretroviral therapy for many patients. Unfortunately, the widespread use of this compound has resulted in unique patterns of abnormal fat accumulation that have been recently described and studied. ##### Methods In these two studies a total of 18 HIV-infected adults were identified and studied. The 8 patients with a “buffalo hump” were on various antiretroviral regimens, four of which included a protease … [1]: {openurl}?query=rft.jtitle%253DLancet%26rft.stitle%253DLancet%26rft.aulast%253DMiller%26rft.auinit1%253DK.%2BD.%26rft.volume%253D351%26rft.issue%253D9106%26rft.spage%253D871%26rft.epage%253D875%26rft.atitle%253DVisceral%2Babdominal-fat%2Baccumulation%2Bassociated%2Bwith%2Buse%2Bof%2Bindinavir.%26rft_id%253Dinfo%253Adoi%252F10.1016%252FS0140-6736%252897%252911518-5%26rft_id%253Dinfo%253Apmid%252F9525365%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [2]: /lookup/external-ref?access_num=10.1016/S0140-6736(97)11518-5&link_type=DOI [3]: /lookup/external-ref?access_num=9525365&link_type=MED&atom=%2Fpediatrics%2F104%2FSupplement_2%2F400.4.atom [4]: /lookup/external-ref?access_num=000072645500014&link_type=ISI

1. Palumbo PE, 2. Raskino C, 3. Fiscus S, 4. et al. (1998) JAMA. 279:756–761. [OpenUrl][1][CrossRef][2][PubMed][3][Web of Science][4] #### Purpose of the Study Pediatric human immunodeficiency virus (HIV) infection may have unique pathogenic features that preclude routine extrapolation of laboratory monitoring results from adult studies. This present study was designed to evaluate the prognostic value of plasma HIV RNA and CD4+ T lymphocyte count for HIV disease progression in infants and children. ##### Methods Data from a “cohort” of 566 infants and children were analyzed. Assays were performed with standard techniques. … [1]: {openurl}?query=rft.jtitle%253DJAMA%26rft.stitle%253DJAMA%26rft.issn%253D0002-9955%26rft.aulast%253DPalumbo%26rft.auinit1%253DP.%2BE.%26rft.volume%253D279%26rft.issue%253D10%26rft.spage%253D756%26rft.epage%253D761%26rft.atitle%253DPredictive%2BValue%2Bof%2BQuantitative%2BPlasma%2BHIV%2BRNA%2Band%2BCD4%252B%2BLymphocyte%2BCount%2Bin%2BHIV-Infected%2BInfants%2Band%2BChildren%26rft_id%253Dinfo%253Adoi%252F10.1001%252Fjama.279.10.756%26rft_id%253Dinfo%253Apmid%252F9508151%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [2]: /lookup/external-ref?access_num=10.1001/jama.279.10.756&link_type=DOI [3]: /lookup/external-ref?access_num=9508151&link_type=MED&atom=%2Fpediatrics%2F104%2FSupplement_2%2F401.1.atom [4]: /lookup/external-ref?access_num=000072366900032&link_type=ISI

Münch J, Rücker E, Ständker L, et al. Cell. 2007;131(6):1059–1071 Seminal Plasma Reduces the Effectiveness of Topical Polyanionic Microbicides Patel S, Hazrati E, Cheshenko N, et al. J Infect Dis. 2007;196(9):1394–1402 PURPOSE OF THE STUDIES. Heterosexual intercourse is the major route of HIV transmission throughout the world. A variety of factors have been identified that are associated with increased transmission, including virus load, lack of circumcision, and the presence of sexually transmitted diseases. One approach to the reduction of male-to-female transmission has been the use of microbicides, and a major effort has been put forth to identify a safe and effective topical microbicide. The purpose of the Münch et al study was to identify factors in semen that might enhance HIV transmission, and the purpose of the Patel et al study was to examine why one of the most promising microbicides tested has failed thus far to reduce transmission in a large controlled trial. STUDY POPULATION. Normal human seminal plasma was studied. METHODS AND RESULTS. In the Münch et al study, investigators screened a complex peptide/protein library derived from human seminal fluid. The authors looked for novel inhibitors and enhancers of HIV infection. They identified fragments of prostatic acidic phosphatase that drastically enhanced HIV infection. Functional and structural analysis showed that these peptides formed amyloid fibrils that captured HIV particles and strongly enhanced the number of productively infected cells in vitro by promoting virion-cell attachment. The authors termed this product “semen-derived enhancer of virus infection” (SEVI). Rats transgenically expressing human CD4 and chemokine receptor 5 (CCR5) are susceptible to HIV infection. In this model, SEVI significantly enhanced the infectivity of HIV in vivo. In the Patel et al study, seminal plasma was shown to dramatically reduce the activity of polyanionic microbicides to reduce infectivity of herpes simplex virus type 2. Further study demonstrated that fibronectin 1 and lactoferrin were the specific factors in seminal plasma that were responsible for this process. In a murine model, this interference in vitro translated to a loss of protection in vivo. CONCLUSIONS. Components of seminal plasma increase HIV infectivity and reduce the effectiveness of topical polyanionic microbicides. REVIEWER COMMENTS. That host factors are involved in HIV replication and transmission is not surprising. However, that amyloid fibrils associated with seminal plasma dramatically increase HIV infectivity was not expected. An increased understanding of the mechanism of this enhancement might assist in overcoming the obstacles noted by Patel et al. An extraordinary effort was put forth to identify a safe and effective microbicide that would prevent transmission of HIV. In vitro and in vivo models indicated that the compound, PRO 2000, would dramatically reduce HIV transmission in vivo. The failure of this approach and the finding that seminal plasma directly interferes with this function dramatically illustrate the need to evaluate seminal plasma as a potential interfering agent in the search for effective microbicides.

Brass AL, Dykxhoorn DM, Benita Y, et al. Science. 2008;319(5865):921–926 PURPOSE OF THE STUDY. The HIV genome encodes only 15 proteins and, therefore, must use multiple host-cell collaborators for successful replication and transmission. Required host-derived proteins include CD4 as the primary virus receptor and chemokine receptors as coreceptors. This study identified multiple other host proteins required for HIV activity. METHODS. Human cells known to be susceptible to HIV were exposed in vitro to HIV. Using small interfering RNAs able to inhibit each known gene in the human genome 1 at a time, the investigators tested whether HIV could establish an infection and copy itself. HIV dependence on >21 000 human genes was examined. RESULTS. More than 250 human genes were identified to be required for efficient HIV replication. Termed “HIV-dependency factors,” the products of these genes are known to participate in a broad array of cellular functions and implicate unsuspected pathways in the virus life cycle. CONCLUSIONS. The extraordinary dependence of HIV on human host proteins for efficient transmission and replication provides many new potential targets for antiretroviral therapy. REVIEWER COMMENTS. An example of targeting host proteins is the use of chemokine receptor 5 (CCR5) inhibitors. Many people with CCR5 deficiency are very resistant to HIV infection yet have limited if any clinical consequences. Maraviroc CCR5 inhibitor is approved for treatment for HIV infection. This study identified many more such potential targets.

Grinsztejn B, Nguyen BY, Katlama C, et al. Presented at: the 46th Interscience Conference on Antimicrobial Agents and Chemotherapy; September 27–30, 2006; San Francisco, CA. Abstract H-16706 PURPOSE OF THE STUDY. Although there are >20 antiretroviral agents available in developed countries, multiple factors limit the construction of combinations of drugs that are capable of effective viral suppression. New agents are clearly needed, particularly for individuals with limited options. MK-0518 is a member of a new class of antiretroviral agents, integrase inhibitors. The purpose of this study was to generate preliminary information on the potency of MK-0518 in the treatment of individuals with triple-class–resistant virus. STUDY POPULATION AND METHODS. There were 178 HIV-infected patients enrolled and assigned to 1 of 3 doses of MK-0518 or placebo. They were followed for 24 weeks, and antiretroviral responses were evaluated. RESULTS. MK-0518 showed remarkable potency at all doses tested. Approximately 60% of the patients who received active drug achieved CONCLUSIONS. MK-0518 had remarkable potent antiretroviral activity in individuals with limited treatment options. The availability of this new class of antiretroviral drug will markedly enhance the options available for patients who are running out of options. REVIEWER COMMENTS. Abstracts presented at scientific meetings are usually not appropriate for a “best-articles-published” series. However, the impact of MK-0518 will be extraordinary. With 3 additional new drugs recently or soon to be available, we will soon have the ability to “salvage” patients with multiresistant virus.

Glass WG, McDermont DH, Lim JK, et al. J Exp Med. 2006;203:35–40 PURPOSE OF THE STUDY. Chemokine receptor 5 (CCR5) is critical for survival of mice infected with West Nile virus (WNV). CCR5Δ32 is a defective CCR5 found predominantly in white individuals. Approximately 1% of the white population in the United States have homozygous CCR5Δ32 and completely lack CCR5 function. Individuals with CCR5Δ32 have an innate resistance to infection with HIV, because most HIV that is transmitted sexually or perinatally uses the CCR5 as a coreceptor with CD4 for HIV attachment to target cells. CCR5 inhibitors are in development, because most individuals with homozygous CCR5Δ32 seem to be immunologically normal. The purpose of this study was to determine if the presence of CCR5Δ32 homozygosity increases the risk for symptomatic WNV infection. STUDY POPULATION AND METHODS. Three cohorts of patients were studied: 2 WNV-positive and 1 WNV-negative but with symptomatic illness in which WNV was considered. Genotypes of CCR5 were defined for each subject in the 3 cohorts. RESULTS. In the group of healthy white random blood donors, CCR5Δ32 homozygotes represented 1% of the total. In contrast, CCR5Δ32 homozygotes represented over 4% of white subjects in the one WNV cohort and 8% in the second cohort. CCR5Δ32 homozygosity was significantly associated with fatal outcome in one of the cohorts. CONCLUSIONS. The authors concluded that CCR5 mediates resistance to symptomatic West Nile infection. REVIEWER COMMENTS. The immune system has evolved over the millennia to provide generally protective functions for the human host. That a particular chemokine receptor was maintained throughout this evolutionary process suggests a survival advantage. One percent of the white population in the United States have a genotype that eliminates functional CCR5. This mutation emerged in northern Europe and probably had no significant negative impact on that population. However, it seems that host defense against WNV depends on sufficient CCR5 engagement. CCR5 blockade is an emerging strategy in the treatment of HIV infection. It is possible that blockade of CCR5 will subsequently result in an increase risk for invasive WNV infection. If the CCR5 inhibitors continue through development, this potential complication must be anticipated.

Purpose of the Study. Latently infected, resting CD4+ T cells provide a reservoir for HIV, and the persistence of these cells prevents the eradication of HIV even in patients who have received highly active antiretroviral therapy (HAART) for prolonged periods. The purpose of this study was to examine the underlying mechanisms by which HIV persists in CD4+ T cells in individuals treated effectively for up to 9 years. Methods. Eleven HIV-infected subjects were studied. These individuals had received effective therapy for an average of 8 years (range: 7.16–9.1 years). None of the patients had experienced detectable plasma viremia after initial suppression. Peripheral blood cells were obtained sequentially on all individuals and studied for the presence of replication-competent virus. Results. All infected subjects carried replication-competent HIV in their CD4+ T cells despite having received prolonged, effectively suppressive antiviral therapy. Contrary to current thinking, substantial higher levels of HIV proviral DNA were found in circulating activated CD4+ T cells when compared with the resting subset. Sequence analysis revealed evidence for cross infection between the resting and activated T-cell compartments, indicating that ongoing reactivation of latently infected, resting CD4+ T cells may occur in these patients. Conclusions. Continual replenishment of the CD4+ T-cell reservoir occurs despite prolonged periods of plasma aviremia. Reviewer Comments. It is only with the elimination of viral reservoirs that HIV infection can be “cured.” Resting T cells harboring proviral DNA do not live forever. However, the rate of viral replenishment in this cell compartment at least equals the natural decline in their numbers. Eliminating this cell reservoir will be a daunting task.

Purpose of the Study. Resting CD4+ T cells are a primary reservoir for HIV. In these cells the HIV is in a latent form and not a target of current antiviral agents. The chromatin-remodeling enzyme histone deacetylase 1 (HDAC1) maintains latency of integrated HIV. This study tested the hypothesis that an inhibitor of HDAC1, valproic acid, would result in depletion of latently infected resting CD4+ T cells. Study Population. Four human volunteers with HIV receiving highly active antiretroviral therapy. Methods. The individual subjects’ antiretroviral therapies were intensified with enfuvirtide, a fusion inhibitor, to minimize the spread of HIV during potential release from latency. The subjects then were treated with oral valproic acid, 500 to 750 mg twice daily, in addition to their antiretroviral therapy, and they were followed for 3 months. Latently infected resting T cells were quantified before and after augmentation of treatment with limiting-dilution culture of resting cells after ex vivo activation. Results. The frequency of resting CD4+ T-cell infection was stable before the addition of enfuvirtide and valproic acid but declined thereafter. This decline was significant in 3 or 4 patients, with a mean reduction of 75% in circulating HIV-infected resting CD4+ T cells. There were no complications of the additional treatments except for the expected injection-site reactions to enfuvirtide. Conclusions. Combination therapy with an HDAC inhibitor and very potent antiretroviral therapy accelerated the reduction in HIV-infected resting T cells. This suggests a new approach to the management of HIV that eventually may result in clearance of HIV from infected individuals. Reviewer Comments. This study received a fair amount of media coverage at the time it was published. It begs the question, can HIV be cured? A 75% reduction in the resting T-cell reservoir seems impressive. However, this was a very short-term study, and the kinetics and degree to which the resting T-cell reservoir was replenished after discontinuation of valproic acid was not reported. In addition, valproic acid, a widely used anticonvulsant, is potentially highly toxic and has “black-box” warnings for hepatotoxicity, teratogenicity, and pancreatitis. Despite the authors’ optimistic conclusions, “this finding, though not definitive, suggests that new approaches will allow the cure of HIV in the future,” use of the “C word” is likely premature.

Purpose of the Study. It was recently established that both acute HIV and its simian counterpart, simian immunodeficiency virus (SIV), are accompanied by dramatic and selective loss of memory CD4+ T cells. This loss has been shown to primarily occur in mucosal tissues. The extent and mechanisms underlying this depletion have not been defined. The purpose of this study was to investigate these questions in a simian model. Methods. Eight rhesus macaque monkeys were infected with a pathogenic strain of SIV. Plasma and tissue samples were collected at various time points by biopsy and necropsy. Lymphocyte subsets were analyzed with standard flow cytometry, and T-cell–associated viral DNA was measured by a highly sensitive quantitative polymerase chain reaction assay. Results. This study demonstrated that in this monkey model, memory CD4+ T cells are depleted in multiple tissues during acute SIV infection. In addition, the loss of these cells is explained by a massive infection of these cells by the virus. Specifically, ∼50% of these cells throughout the body are infected by SIV at the peak of infection, and most of the infected cells disappear within several days. Alternative mechanisms are not required. This depletion occurs to a similar extent in all tissues. Conclusions. Acute immunodeficiency virus infection results in the loss of ∼50% of all memory T cells within days of infection. This and other studies strongly suggest that this loss, at least in adult animals and humans, is irreversible. Reviewer Comments. This study confirms and extends previous findings demonstrating massive memory T-cell loss during acute HIV or SIV infection. The extent to which this loss is recoverable is likely to be very limited. Most interesting is that these authors also noted that naive T cells are highly resistant to SIV infection. These observations are particularly important for infants infected with HIV. Young infants have fewer memory CD4+ T cells, and, therefore, their loss may not be as critical in newborns. In addition, the thymus in young children may be more capable of reconstituting memory T-cell functions if HIV is completely suppressed early. Similar studies should be performed on infant laboratory animals to determine the extent to which recovery is likely in infected children.

Lambert JS, Harris R, Stiehm R, et al. J Acquir Immune Defic Syndr . 2003;34:512–519 The diagnosis of HIV infection in a newborn exposed to HIV in utero is a challenge. In the early years of the epidemic, HIV clinicians monitored the decline of HIV antibody levels for up to 2 years after birth to confirm that a child was not HIV-infected. HIV infection in infants is now typically made by the detection of …

Laderman MM, Veazey RS, Offord R, et al. Science . 2004;306:485–487 Topical agents that prevent transmission of HIV across mucosae during sexual activity are urgently needed, because the vast majority of HIV infections are acquired through transmission across mucosal surfaces. However, the mechanisms of HIV entry at vaginal sites of infection are poorly understood. The chemokine receptor CCR5 serves as an essential coreceptor for HIV entry into target cells. Individuals who …

Mangeat B, Turelli P, Caron G, et al. Nature. 2003;424:99–102 Innate intracellular antiretroviral defense mechanisms have been described. Viral infection requires that these lines of defense be overcome, and this task is usually accomplished by specialized viral proteins. The virus infectivity factor (Vif) protein of human immunodeficiency virus (HIV) is required to counter the antiviral activity of a protein expressed …

Rousseau CM, Nduati RW, Richardson BA, et al. J Infect Dis. 2003;187:741–747 Transmission of human immunodeficiency virus (HIV) via breastfeeding may occur throughout lactation. In developing countries, where >90% of HIV-exposed children live, safe alternatives to breastfeeding are not available. An understanding of the dynamics of breast milk virus levels and the correlation of breast milk virus levels with mother-to-child transmission is essential for the development of effective interventions. A total of …

Ananworanich J, Nuesch R, Le Braz M, et al. AIDS. 2003;17:F33–F37 Although highly active antiretroviral therapy (HAART) has dramatically improved the duration and quality of life of human immunodeficiency virus (HIV)-infected individuals, an increasing number of serious complications are being identified among patients who are treated with these agents for long periods of time. Strategies that reduce the total drug exposure among infected patients while maintaining the stability of HIV and T cell levels would be welcomed. Scheduled or structured …

Starc TJ, Lipshultz SE, Easley KA, et al. J Pediatr . 2002;141:327–334 Human immunodeficiency virus (HIV) infection may be associated with severe cardiac complications. The objective of this study was to describe the 5-year cumulative incidence of cardiac abnormalities in HIV-infected children. A prospective cohort was developed involving children from 10 hospitals throughout the United States. Group I included 205 HIV-infected children enrolled at a median age of 1.9 years and group II consisted of 600 HIV-exposed …