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Background: A wide range of host restriction factors (RF) become upregulated upon HIV-1 infection to suppress viral infectivity and may aid viremic control in vivo. This cross-sectional study evaluated HIV-1 RFs and dependency factors in HIV infected individuals with progressive or non-progressive infection, as well as in early and late treated cohorts that exhibit different viro-immunological profiles due to differences in timing of treatment-initiation. Methods: The expression profile of IFIT1, MX1, APOBEC3G, SAMHD1, BST2 (encoding TETHERIN), TRIM5, MX2, SLFN11, PAF1, PSIP1 (encoding LEDGF/p75), and NLRX1 was measured by qPCR in 104 HIV-1 positive individuals: seroconverters (SRCV; n =19), long term non-progressors (LTNP; n =17), viremic progressors (VP; n =12), patients treated during seroconversion (Early treated; n =24) or chronic infection (Late treated; n =32), and non-infected controls. Findings: Expression levels of early treated HIV-1 positive individuals were significantly upregulated in comparison to late treated patients (IFIT1: p=0.0003; MX1: p=0.008; APOBEC3G: p=0.002; SAMHD1: p=0.0008; SLFN11: p

Persistence of HIV through integration into host DNA in CD4(+) T cells presents a major barrier to virus eradication. Viral integration may be curtailed when CD8(+) T cells are triggered to kill infected CD4(+) T cells through recognition of histocompatibility leukocyte antigen (HLA) class I-bound peptides derived from incoming virions. However, this has been reported only in individuals with "beneficial'' HLA alleles that are associated with superior HIV control. Through interrogation of the pre-integration immunopeptidome, we obtain proof of early presentation of a virion-derived HLA-A*02:01-restricted epitope, FLGKIWPSH (FH9), located in Gag Spacer Peptide 2 (SP2). FH9-specific CD8(+) T cell responses are detectable in individuals with primary HIV infection and eliminate HIV-infected CD4(+) T cells prior to virus production in vitro. Our data show that non-beneficial HLA class I alleles can elicit an effective antiviral response through early presentation of HIV virion-derived epitopes and also demonstrate the importance of SP2 as an immune target.

Background: Antiretroviral therapy (ART) cannot cure HIV infection because of a persistent reservoir of latently infected cells. Approaches that force HIV transcription from these cells, making them susceptible to killing—termed kick and kill regimens—have been explored as a strategy towards an HIV cure. RIVER is the first randomised trial to determine the effect of ART-only versus ART plus kick and kill on markers of the HIV reservoir. Methods: This phase 2, open-label, multicentre, randomised, controlled trial was undertaken at six clinical sites in the UK. Patients aged 18–60 years who were confirmed as HIV-positive within a maximum of the past 6 months and started ART within 1 month from confirmed diagnosis were randomly assigned by a computer generated randomisation list to receive ART-only (control) or ART plus the histone deacetylase inhibitor vorinostat (the kick) and replication-deficient viral vector T-cell inducing vaccines encoding conserved HIV sequences ChAdV63. HIVconsv-prime and MVA.HIVconsv-boost (the kill; ART + V + V; intervention). The primary endpoint was total HIV DNA isolated from peripheral blood CD4+ T-cells at weeks 16 and 18 after randomisation. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, NCT02336074. Findings: Between June 14, 2015 and Jul 11, 2017, 60 men with HIV were randomly assigned to receive either an ART-only (n=30) or an ART + V + V (n=30) regimen; all 60 participants completed the study, with no loss-to-follow-up. Mean total HIV DNA at weeks 16 and 18 after randomisation was 3·02 log10 copies HIV DNA per 106 CD4+ T-cells in the ART-only group versus 3·06 log10 copies HIV DNA per 106 CD4+ T-cells in ART + V + V group, with no statistically significant difference between the two groups (mean difference of 0·04 log10 copies HIV DNA per 106 CD4+ T-cells [95% CI −0·03 to 0·11; p=0·26]). There were no intervention-related serious adverse events. Interpretation: This kick and kill approach conferred no significant benefit compared with ART alone on measures of the HIV reservoir. Although this does not disprove the efficacy kick and kill strategy, for future trials enhancement of both kick and kill agents will be required.

Background The HIV-1 proviral genome harbors multiple CpG islands (CpGIs), both in the promoter and intragenic regions. DNA methylation in the promoter region has been shown to be heavily involved in HIV-1 latency regulation in cultured cells. However, its exact role in proviral transcriptional regulation in infected individuals is poorly understood or characterized. Moreover, methylation at intragenic CpGIs has never been studied in depth. Results A large, well-characterized HIV-1 patient cohort (n = 72), consisting of 17 long-term non-progressors and 8 recent seroconverters (SRCV) without combination antiretroviral therapy (cART), 15 early cART-treated, and 32 late cART-treated patients, was analyzed using a next-generation bisulfite sequencing DNA methylation method. In general, we observed low level of promoter methylation and higher levels of intragenic methylation. Additionally, SRCV showed increased promoter methylation and decreased intragenic methylation compared with the other patient groups. This data indicates that increased intragenic methylation could be involved in proviral transcriptional regulation. Conclusions Contrasting in vitro studies, our results indicate that intragenic hypermethylation of HIV-1 proviral DNA is an underestimated factor in viral control in HIV-1-infected individuals, showing the importance of analyzing the complete proviral genome in future DNA methylation studies.

Important data on the social, epidemiological and clinical aspects of HIV-1, comorbidities and hepatitis as well as data on novel antiretroviral agents and the cure agenda were presented at AIDS 2018. This report covers some of the highlights.

The aim of this study was to assess cardiovascular diagnoses and management in a cohort of patients diagnosed with HIV, and the performance of a joint HIV/Cardiology Clinic in a tertiary hospital setting. A retrospective analysis was performed on all patients referred to a joint HIV/Cardiology Clinic at our hospital. Data on 120 patients were collected. In this predominantly male population (male 101 and female 19) coronary artery disease (CAD) was the most common diagnosis (34%, n = 41). Other diseases included hypertension (12.5%, n = 15), cardiomyopathy (12.5%, n = 15) and arrhythmia (6%, n = 8). The majority of remaining cases included non-cardiac chest pain and palpitations. In addition to usual primary and secondary preventive measures for CAD, complex procedures, such as percutaneous coronary intervention, cardiac resynchronisation therapy for left ventricular systolic dysfunction and radiofrequency ablation for arrhythmias, were carried out. Overall cardiovascular mortality among the group was 2.5% (n = 3) over 4 years. The results indicate the efficacy of a specialist joint HIV/Cardiology Clinic in diagnosing and managing various cardiac conditions in a complex cohort of patients with HIV.

This study examined the relationship between the severity of acute human immunodeficiency virus type 1 (HIV-1) illness and disease progression and death. The population included 218 patients with acute HIV-1 illness and 41 asymptomatic patients who underwent HIV-1 seroconversion; the patients were followed up prospectively. We analyzed progression to Centers for Disease Control and Prevention clinical categories B and C (AIDS-defining conditions) and death according to an additive clinical score (CS) based on six predictive clinical features at the time of acute HIV-1 infection. Compared with patients with a CS of 0 (asymptomatic patients), those with a CS of 3-4 and 5-6 had faster progression to category B disease (adjusted hazard ratio [HR], 1.39; 95% confidence interval [CI], 1.01-1.92; and HR, 1.80; 95% CI, 1.34-2.40; respectively); those with a CS of 5-6 had faster progression to category C disease (HR, 1.37; 95% CI, 1.01-1.89) and death (HR, 2.05; 95% CI, 1.27-3.32). Thus, the number of symptoms and signs at the time of acute HIV-1 illness affects disease progression and survival, even in symptomatic patients who have undergone seroconversion.

Therapy failure due to drug resistance development is a common phenomenon in HIV-infected patients. However, when the drug pressure leads to the earliest selection of drug-resistant HIV-1 populations is still unclear. In this study, the extent to which selection of the HIV-1 reverse transcriptase M184I/V mutations occur during the initial phase of viral decay in treatment-naive HIV-1 infected patients receiving antiretroviral therapy (ART) was examined. Plasma virus from three cohorts of treatment-naive patients initiating quadruple (n = 43), triple (n = 14) or dual (n = 15) lamivudine-containing ART were analyzed for M184I/V during the first 6 months of therapy using direct sequencing and a sensitive selective real-time PCR method. Among quadruple ART patients, who all were treated at primary HIV-1 infection, only one patient developed M184V after 6 weeks of therapy, having had wild-type virus at baseline. No mutations were found in chronically infected patients on triple ART. In patients on dual therapy, M184I/V mutants were found frequently. Selection of M184I/V mutants was found to be rare during the initial phase of viral decay after initiation of ART in adherent patients given a three or four-drug combination, in contrast to those receiving a less potent regimen. The results suggest that triple and quadruple lamivudine + PI or PI/r containing ART given to treatment-naive adherent patients is potent enough to prevent development of resistance during the first months of therapy. J. Med. Virol. 81:1–8, 2009. © 2008 Wiley-Liss, Inc.

The optimal time to start antiretroviral therapy for HIV-infected patients remains unknown [1-4]. Leaving public health considerations regarding transmission aside, if we are indeed able to diagnose HIV infection in patients at a very early stage, should we intervene with antiviral agents and, if so, for how long [5-7]? What is the potentially achievable long-term impact of highly active antiretroviral therapy (HAART) initiated around the time of HIV seroconversion, if such treatment is subsequently discontinued: lowering of the viral set point, preservation of CD4' T cells, a decrease in rates of disease progression, long-term control of HIV viremia, or even viral eradication [8-10]? In contrast, one may argue that very early initiation of HAART may still be provided too late to have a major impact, because virus-induced immunopathogenesis has already taken hold [11-13]. This realization would justify a more conservative treatment approach and the initiation of HAART only during chronic infection, because this approach still allows for substantial immune reconstitution in terms

Objectives: To study the long-term CD4 cell responses to highly active antiretroviral therapy (HAART) in treatment-naive patients whose viral loads remained below 500 copies/ml for prolonged periods. Design: A total of 237 patients whose viral loads remained below 500 copies/ml for one year or more. Median follow-up was 1.9 years. Methods: CD4 cell counts were analysed to investigate long-term immunological response using mixed-effects models with the slope allowed to change after 1, 12 and 24 months of HAART. Results: The median baseline CD4 cell count was 175 cells/mm 3 . After an initial rapid increase in the first month after HAART (97.2 cells/mm 3 a month), increases in CD4 cell counts continued less rapidly (11.6 cells/mm 3 a month). This increase slowed by 2.4 cells/mm 3 a month after one year. CD4 cell counts continued increasing after 2 years, but the rate of increase again slowed (estimated slope at 2 years 5.4 cells/mm 3 a month; decrease in slope from year 2 compared with years 1-2 3.7 cell/mm 3 a month). A total of 198 out of 211 patients (94%) with measurements at baseline and one year experienced an increase in CD4 cell counts in this interval; 81 and 67% had an increasing slope between 1 and 2 and 2 and 3 years, respectively. By the end of follow-up, CD4 cell counts had increased by 319 cells/mm 3 , and were more than 500 cells/mm 3 in 40% of patients. Conclusion: Although the rate of immune recovery slowed after 2 years, CD4 cell counts rose in most and began to return to levels seen in HIV-negative individuals.

In the absence of an effective prophylactic vaccine and successful viral eradication strategies, the burden of human immunodeficiency virus type 1 (HIV-1) infection and disease continues to grow worldwide. The events characterizing primary HIV-1 infection and the early stages of the infection have been the focus of extensive research addressing the modalities of HIV-1 transmission. A thorough understanding of the early viral and host interactions leading to the establishment of productive infection will provide the necessary evidence base for developing successful prophylactic and therapeutic tools, including drug regimens, vaccines, and microbicides, and for guiding clinical management and the optimal time for the initiation of antiretroviral therapy. From a global perspective, among the various possible modes of acquisition, the majority of new HIV-1 infections occur through sexual transmission across mucosal barriers. Early after infection, HIV-1 strains appear to be genetically homogenous but rapidly diversify into a swarm of related but genetically divergent variants that compose the viral quasispecies. The highest degree of diversification is observed in the envelope glycoprotein 120 (gp120), the target of strong immune responses, including T-cell‐mediated and neutralizing antibodies [ 1 , 2 ]. There is substantial evidence to indicate that the diverse quasispecies

BACKGROUND: Highly active antiretroviral therapy (HAART) is now widely used in clinical practice and gives rise to a range of immunological, virological and clinical responses. OBJECTIVES: To describe the immunological, virological and clinical response to HAART and to examine the frequency of modification of the HAART regimen among patients from a single treatment centre. METHODS: Kaplan-Meier estimation and incidence rates were used to describe responses to HAART (a protease inhibitor or non-nucleoside drug in addition to at least two nucleoside analogues) among 421 patients from the Royal Free Hospital in London. RESULTS: The median CD4 cell count at starting HAART was 186 x 10(6) cells/l [interquartile range (IQR) 76-310] and viral load was 5.13 log10 copies/ml (IQR 4.66-5.56). At 6 months after starting HAART, 51.1% of patients were estimated to have experienced a 100 x 10(6) cells/l increase in CD4 cell count; the median time for viral load to fall below 400 copies/ml was 3.7 months (95% confidence interval 3.2-4.4). At 6 months after the first viral load was 400 copies/ml and 12.4% were estimated to have failed if the more stringent definition of two viral loads above the limit of detection was used. Compared with the pre-HAART era, the incidence of death among patients on HAART was one sixth of that level; new AIDS-defining illnesses was one seventh; and hospital admissions was one fifth. In total, 141 patients (33.5%) stopped at least one of the antiretroviral agents included as part of their HAART regimen; the occurrence of side effects was the most common reason (n = 63; 44.7%). CONCLUSION: A good response occurred to an initial HAART regimen. There was a high rate of virological relapse, which varied considerably according to the definition of failure used. Even so, the rates of clinical progression and hospital admissions observed to date were low. Further follow-up of these patients is required to determine their long-term immunological, virological and clinical outcome.

The International Congress on Targeting Ebola 2015 was held on 28–29 May 2015 at the Pasteur Institute in Paris ( www.targeting-ebola.com). The meeting was organised in partnership with the COPED of the French Academy of Sciences, the French Task Force Group for Ebola, the Pasteur Institute and the Task Force for Infectious Diseases. Publication of a summary of the meeting by the organisers is anticipated in an open-access journal. This paper aims to provide a brief overview of the main discussion points during the meeting. This meeting brought together more than 300 experts in the field of ebola virus disease (EVD) from Europe, Africa, Asia and the US to discuss advances in combatting the virus. Their expertise encompassed infectious diseases, basic science, epidemiology, anthropology, virology, immunology, and included representatives from industry (both diagnostics and therapeutics), non-governmental organisations (NGOs) such as Medecins Sans Frontieres (MSF), funding agencies such as the Gates Foundation and Fondation Merieux, and the World Health Organization (WHO). The meeting aimed to cover diverse topics including viral pathogenesis, virus–host interactions, epidemiology, cultural aspects of the disease, diagnostic tools, treatment protocols, vaccines and operational research.

Sequences of the human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) domain were determined by direct sequencing of HIV-1 RNA in successive plasma samples from eight seroconverting patients infected with virus bearing the T215Y/F amino acid substitution associated with zidovudine (ZDV) resistance. At baseline, additional mutations associated with ZDV resistance were detected. Three patients had the M41L amino acid change, which persisted. Two patients had both the D67N and the K70R amino acid substitutions; reversion to the wild type was seen at both positions in one of these patients and at codon 70 in the other one. Reversion to the wild type at codon 215 was observed in only one of eight patients. Unusual amino acids, such as aspartic acid (D) and cysteine (C), appeared at position 215 in four patients during follow-up. These variants isolated by coculturing were sensitive to ZDV. Overgrowth of these variants suggests that they have better fitness than the original T215Y variant. Intraindividual nucleoside substitutions over time were 10 times more frequent in codons associated with ZDV resistance (41, 67, 70, 215, and 219) than in other codons of the RT domain. The predominance of nonsynonymous substitutions observed over time suggests that most changes reflect adaptation of the RT function. The variance in sequence evolution observed among patients, in particular at codon 215, supports a role for chance in the evolution of the RT domain.

Background It is possible that antiretroviral treatment given early during primary infection with the human immunodeficiency virus (HIV) may reduce acute symptoms, help preserve immune function, and improve the long-term prognosis. Methods To assess the effect of early antiviral treatment, we conducted a multicenter, double-blind, placebo-controlled trial in which 77 patients with primary HIV infection were randomly assigned to receive either zidovudine (250 mg twice daily; n = 39) or placebo (n = 38) for six months. Results The mean time from the onset of symptoms until enrollment in the study was 25.1 days. Among the 43 patients who were still symptomatic at the time of enrollment, there was no appreciable difference in the mean (±SE) duration of the retroviral syndrome between the zidovudine group (15.0±4.1 days) and the placebo group (15.8±3.6 days). During a mean follow-up period of 15 months, minor opportunistic infections developed in eight patients: oral candidiasis in four, herpes zoster in two, ...

BackgroundIntervention with antiretroviral treatment (ART) and control of viral replication at the time of HIV-1 seroconversion may curtail cumulative immunological damage. We have therefore hypothesized that ART maintenance over a very prolonged period in HIV-1 seroconverters could induce an immuno-virological status similar to that of HIV-1 long-term non-progressors (LTNPs).Methodology/principal findingsWe have investigated a cohort of 20 HIV-1 seroconverters on long-term ART (LTTS) and compared it to one of 15 LTNPs. Residual viral replication and reservoirs in peripheral blood, as measured by cell-associated HIV-1 RNA and DNA, respectively, were demonstrated to be similarly low in both cohorts. These two virologically matched cohorts were then comprehensively analysed by polychromatic flow cytometry for HIV-1-specific CD4(+) and CD8(+) T-cell functional profile in terms of cytokine production and cytotoxic capacity using IFN-γ, IL-2, TNF-α production and perforin expression, respectively. Comparable levels of highly polyfunctional HIV-1-specific CD4(+) and CD8(+) T-cells were found in LTTS and LTNPs, with low perforin expression on HIV-1-specific CD8(+) T-cells, consistent with a polyfunctional/non-cytotoxic profile in a context of low viral burden.ConclusionsOur results indicate that prolonged ART initiated at the time of HIV-1 seroconversion is associated with immuno-virological features which resemble those of LTNPs, strengthening the recent emphasis on the positive impact of early treatment initiation and paving the way for further interventions to promote virological control after treatment interruption.

This review focuses on some of the recent advances in the understanding of HIV immunopathogenesis and the diagnosis and treatment of several autoimmune conditions associated with HIV in the era of potent antiretroviral therapy.Chronic immune activation with progressive immune exhaustion are central features of HIV pathogenesis. The role of self-reactive T cells in the generation and maintenance of this process has recently been described. The understanding of the impact of immune dysregulation on the generation of autoimmune phenomena in HIV infection remains incomplete. The diagnosis of autoimmune diseases in the context of HIV is often difficult due to similarities in clinical presentations and laboratory markers. The antiretroviral therapy-associated immune reconstitution syndrome can present as autoimmune disease.The cause, frequency and prognosis of autoimmune conditions associated with HIV infection remain somewhat uncertain. Their management is often empirical with the use of novel immunosuppressive medication.

Purpose of review Treatment of primary HIV-1 infection may alter the natural history of HIV-1 infection and delay the need for chronic antiretroviral therapy; it may also be a public health measure. We discuss the results of therapeutic trials and cohort studies, the occurrence of transmitted drug resistance, and recent findings in terms of immunopathogenesis and decay of viral reservoirs. Recent findings Events at the time of primary HIV-1 infection are understood to set the scene for persistence of immunologic damage and chronic immune activation, with a rapid viral onslaught primarily on memory CD4+ T cells at mucosal effector sites. The initiation of antiretroviral therapy at primary HIV-1 infection has been associated with a high degree of undetectable viremia in compliant patients and substantial decay of reservoirs in peripheral blood. The degree of immune reconstitution at the gut mucosal level, however, does not appear to be comparable to that in peripheral blood. Summary Recent insights into the long-term consequences of the early burst of HIV-1 replication – together with transmitted drug resistance, onward transmission, and the possibility of decay of viral reservoirs – are important steps in helping to design future therapeutic strategies in primary HIV-1 infection in an era of intense drug and vaccine development.

PURPOSE OF REVIEW: The antiretroviral therapy efficacy remains unquestioned, though associated with drug resistance, toxicity and high costs. Several strategies of therapeutic immunization are being explored to limit time on treatment and prevent disease progression by increasing the immunological control of HIV. RECENT FINDINGS: Research on immune correlates of protection suggests that boosting the HIV-specific T cells with vaccines should combine amplification of specific effector and memory T cells. Trials with inactivated virus particles, peptides or naked DNA boosted HIV-specific CD4 T cells and showed moderate effects on virus replication but require, however, adjuvantation or combination with other vaccines. Most clinical trials evaluating recombinant live vectors used so far the HIV-recombinant canarypox with immunogenicity for HIV-specific CD4 and CD8 T cells. Significant virus control or prolongation of treatment interruptions was repeatedly observed in the antiretroviral therapy-treated chronically infected patients but not in the acutely infected ones. Infusions of autologous dendritic cells loaded with inactivated autologous HIV showed promising results in chronically infected patients. SUMMARY: The better efficacy of therapeutic immunization in chronic infection raises questions while those encouraging, though still modest, results prompt development of stronger vaccine candidates to optimize such strategy.

Therapy failure due to drug resistance development is a common phenomenon in HIV-infected patients. However, when the drug pressure leads to the earliest selection of drug-resistant HIV-1 populations is still unclear. In this study, the extent to which selection of the HIV-1 reverse transcriptase M184I/V mutations occur during the initial phase of viral decay in treatment-naïve HIV-1 infected patients receiving antiretroviral therapy (ART) was examined. Plasma virus from three cohorts of treatment-naïve patients initiating quadruple (n = 43), triple (n = 14) or dual (n = 15) lamivudine-containing ART were analyzed for M184I/V during the first 6 months of therapy using direct sequencing and a sensitive selective real-time PCR method. Among quadruple ART patients, who all were treated at primary HIV-1 infection, only one patient developed M184V after 6 weeks of therapy, having had wild-type virus at baseline. No mutations were found in chronically infected patients on triple ART. In patients on dual therapy, M184I/V mutants were found frequently. Selection of M184I/V mutants was found to be rare during the initial phase of viral decay after initiation of ART in adherent patients given a three or four-drug combination, in contrast to those receiving a less potent regimen. The results suggest that triple and quadruple lamivudine + PI or PI/r containing ART given to treatment-naïve adherent patients is potent enough to prevent development of resistance during the first months of therapy.

The benefit of transient combination antiretroviral treatment (CART) during acute HIV infection is uncertain. We used the seroconverter database CASCADE to provide a historical comparison for the Quest trial, in which 79 subjects with acute HIV infection received CART for an average of 2.6 years, and 17.7% (95% confidence interval [CI]: 10.9-27.6) fulfilled the primary endpoint of VLor =1,000 copies/ml 24 weeks after CART discontinuation.We estimated the prevalence of VLor =1,000 copies/ml three years after seroconversion and prior to any ART among 385 sexually infected subjects in CASCADE who seroconverted between 1988 and 1996. We conducted a pre-specified comparison with the recently published Quest results, and considered potential biases.The prevalence of VLor =1,000 copies/ml at year three in CASCADE was 10.1% (95% CI: 7.5-13.5) (absolute difference compared to 17.7% in Quest: 7.6%; 95% CI: -0.1-17.8; P=0.053). In CASCADE, VLor =1,000 copies/ml was less common among homosexual and heterosexual men compared with women (8.5%, 7.3% and 17.6% respectively) and in subjects with symptomatic infection compared with those without (6.2% and 12.6%, respectively). As Quest had a much greater proportion of symptomatic subjects than CASCADE, any true difference in VL might be underestimated. Therefore this comparison suggests that transient CART in acute infection might result in a modest increase in the probability of low VL subsequently. However, several factors mitigate this conclusion. First, this historical comparison might be subject to other unmeasured confounders. Second, a comparison of median VL at the same time point was not significant (4.02 copies/ml and 4.20 copies/ml in Quest and CASCADE, respectively; P=0.55). Finally, additional analysis suggested that the observed difference in low VL at year three would be consistent with an immediate effect of CART only - a delay of usual VL decline without additional benefit.A small but significant proportion of seroconverters have low VL without ART. Transient CART in acute infection might increase the probability of low VL after treatment discontinuation, but such an effect is likely to be modest, and might represent a delay of natural history rather than a long-term therapeutic benefit.

Background The success of clinical care for human immunodeficiency virus infection may vary across demographic groups, because of patient- and health care–related factors. Methods A total of 2386 patients sexually infected with the human immunodeficiency virus were seen in a London clinic from July 1, 1999, to December 31, 2004. We examined demographic variation and trends over time in the prevalence of the following: (1) a CD4 cell count of 200/μL or less; (2) a viral load of greater than 50 copies/mL among patients receiving antiretroviral therapy (ART); and (3) a viral load of greater than 50 copies/mL among patients receiving ART for 24 weeks or longer. Results Subjects were homosexual men (63.1%), white heterosexual men (4.3%) and women (5.1%), and black African or other ethnicity heterosexual men (10.2%) and women (17.3%). The CD4 cell count at the first clinic visit was highest among homosexual men and lowest among black African heterosexual men. From 1999 to 2004, ART use increased from 61.9% to 75.5%. The prevalence of a CD4 cell count of 200/μL or less decreased from 19.6% to 9.0%. The prevalence of a viral load of greater than 50 copies/mL decreased from 36.9% to 14.5% among patients receiving ART, and from 31.2% to 10.1% among patients receiving ART for 24 weeks or longer. Demographic variation in the prevalence of each outcome was apparent among men throughout the period: homosexual men had the most favorable profile, and black African heterosexual men had the least favorable profile. Differences were much greater for low CD4 cell count than for raised viral load while receiving ART. There was no consistent demographic variation among women. Favorable trends over time occurred within each demographic group, and were as strong among black African patients as among other subgroups. Conclusions The success of clinical care for human immunodeficiency virus infection increased substantially from 1999 to 2004 in this routine clinic population. All demographic subgroups benefited from improvements, despite ongoing differences in the prevalence of immunosuppression.

Objective To study innate and adaptive immune responses in gut-associated lymphoid tissue (GALT) as well as peripheral lymphoid tissue (pLT) obtained from individuals with acute HIV-1 infection syndrome. Design The expression of chemokines [regulated upon activation: normal T cell expressed/secreted (RANTES), macrophage-inflammatory protein (MIP) 1alpha/beta], cytokines (IL-1beta, TNF-alpha, IL-12, IL-4, IL-10, IL-2, IFN-gamma) and cytotoxic effector molecules (granzyme A, perforin) and cell marker (CD8) were analysed at the single cell level in GALT and pLT of patients experiencing acute HIV-1 infection (day -3 to 48 days from onset of acute symptoms). Results Substantial pro-inflammatory immune responses (TNF-alpha, IL-1beta, IL-12) and expansion in the CD8 T-cell population were noted in both compartments compared with uninfected controls. This was associated with an early increased expression of beta-chemokines (RANTES, MIP-1alpha/beta) and granzyme, but not with an increase in the expression of perforin. The upregulation of IL-2, IL-12 and IL-4 was noted in both pLT and GALT, whereas IL-10 expression was mainly increased in GALT. Conclusion Taken together, these findings demonstrate that there was a broad and early immune activation in GALT and pLT during acute HIV-1 infection. The relative lack of perforin expression in both GALT and pLT, however, questions the functional efficacy of the observed immune activation in generating cytotoxic T cells that were able to eliminate HIV-infected cells.

BACKGROUND Treatment strategies that would induce durable virological control of human immunodeficiency virus (HIV)-1 in the absence of continued antiretroviral therapy (ART) are highly desirable.METHODS. We assessed, in a randomized, double-blind, placebo-controlled trial, whether the addition of therapeutic vaccines (ALVAC-HIV [vCP1452] or ALVAC-HIV and Remune) to ART initiated during acute infection could increase the probability of having a plasma viral load

Background. Highly active antiretroviral therapy (HAART) results in an improvement in immunologic function. We sought to investigate the factors associated with increases in CD4 cell count among human immunodeficiency virus (HIV)-positive antiretroviral-naive patients starting HAART. Methods. Five hundred ninety-six subjects were followed for a median of 2.5 years (interquartile range, 1.0-4.0 years). Factors associated with changes in CD4 cell counts in the first 3 months of HAART and from 3 months onwards were analyzed. Results. After 6, 12, and 24 months of HAART, the median increases in CD4 cell counts were 114, 181, and 248 cells/mm 3 , respectively; 84%, 84%, and 80% of subjects had a virus load of

International audience; The 2014 International Symposium on HIV and Emerging Infectious Diseases (ISHEID) provided a forum for investigators to hear the latest research developments in the clinical management of HIV and HCV infections as well as HIV cure research. Combined anti-retroviral therapy (c-ART) has had a profound impact on the disease prognosis and transformed this infection into a chronic disease. However, HIV is able to persist within the infected host and the pandemic is still growing. The main 2014 ISHEID theme was, hence "Together for a world without HIV and AIDS". In this report we not only give details on this main topic but also summarize what has been discussed in the areas of HCV coinfection and present a short summary on currently emerging viral diseases.

The progression of 'naive' and 'memory' T-cells and the T-cell receptor Vbeta (TCR Vbeta) repertoire dynamics within the peripheral CD4+ T-cell compartment were studied in individuals following HIV seroconversion. Profound TCR Vbeta repertoire perturbations were observed within the CD4+ T-cell pool in treatment-naive patients regardless of their levels of viremia during the first 6-8 months after seroconversion. The ratio of 'naive' to 'memory' CD4+ T-cells as well as the TCR Vbeta repertoire dynamics did not appear to correlate with absolute numbers of CD4 T-cells.

The purpose of this study was to describe the frequency and duration of clinical features at the time of acute human immunodeficiency virus type 1 (HIV-1) disease in 218 patients with documented symptomatic primary HIV-1 infection. The mean duration of acute HIV-1 disease was 25.1 days (median, 20.0 days) and did not differ by gender, age, and risk factor. The frequency and mean duration of clinical features occurring in >50% of patients were as follows: fever, 77.1% and 16.9 days; lethargy, 65.6% and 23.7 days; cutaneous rash, 56.4% and 15 days; myalgia, 54.6% and 17.7 days; and headache, 50.9% and 25.8 days. Only 15.6% of patients presented with a typical mononucleosis-like illness (MLI) defined as fever, pharyngitis or sore throat, and cervical adenopathy, and 10% had no features of an MLI. A meningitis-like syndrome occurred in 20 patients (9.2%). Acute HIV-1 disease is more diverse than previously reported, and the absence of fever or other MLI features does not rule out acute HIV-1 disease.

Bacillary angiomatosis (BA) is newly reported infectious disease observed mainly in HIV-infected patients, caused by a small gram-negative bacillus of the Rochalimea genus. From a purely dermatological presentation similar to that of Kaposi's sarcoma, it may evolve into a systemic disease. Bone lesions seem fairly frequent. We report a case of an isolated osteolytic lesion due to the BA bacillus.

To evaluate the concentration of circulating RNA (viraemia) in patients with symptomatic primary HIV infection and relate it to sero-immunological parameters.Semiquantitation of circulating HIV RNA and proviral HIV DNA was performed using the polymerase chain reaction. Circulating HIV RNA concentrations were expressed as virus equivalent (RNA copies/2) per ml serum.The mean CD4+ lymphocyte count for 19 patients with symptomatic primary HIV infection was 583 x 10(6)/l. Fifteen (79%) patients had detectable levels of p24 antigen (median 462 pg/ml). Circulating HIV RNA (median 2.3 x 10(7) virus equivalent/ml serum) and proviral HIV DNA (median 3630 copies/ml blood) were detected in all samples tested. Follow-up data for five patients (200-1600 days) showed a 1-3 log reduction in circulating RNA within 2 months. Later, circulating RNA concentrations were consistently greater than 10(3) virus equivalent/ml serum. Within 10 days no p24 antigen was detectable. Levels of CD4+ cells varied markedly from patient to patient during the follow-up and, in this small group, no evident correlation was observed between circulating RNA levels and CD4+ lymphocyte counts.High concentrations of circulating RNA (viraemia) were present in 19 patients with symptomatic primary HIV infection. Although a decrease in viraemia was observed during the following 2 months, viraemia persisted in all patients with long-term follow-up. This suggests that active viral replication is a continuous process in HIV-infected patients.

Objective The benefit of transient combination antiretroviral treatment (CART) during acute HIV infection is uncertain. We used the seroconverter database CASCADE to provide a historical comparison for the Quest trial, in which 79 subjects with acute HIV infection received CART for an average of 2.6 years, and 17.7% (95% confidence interval [CI]: 10.9–27.6) fulfilled the primary endpoint of VL≤1,000 copies/ml 24 weeks after CART discontinuation. Methods We estimated the prevalence of VL ≤1,000 copies/ml three years after seroconversion and prior to any ART among 385 sexually infected subjects in CASCADE who seroconverted between 1988 and 1996. We conducted a pre-specified comparison with the recently published Quest results, and considered potential biases. Results and discussion The prevalence of VL ≤1,000 copies/ml at year three in CASCADE was 10.1% (95% CI: 7.5–13.5) (absolute difference compared to 17.7% in Quest: 7.6%; 95% CI: -0.1–17.8; P=0.053). In CASCADE, VL≤1,000 copies/ml was less common among homosexual and heterosexual men compared with women (8.5%, 7.3% and 17.6% respectively) and in subjects with symptomatic infection compared with those without (6.2% and 12.6%, respectively). As Quest had a much greater proportion of symptomatic subjects than CASCADE, any true difference in VL might be underestimated. Therefore this comparison suggests that transient CART in acute infection might result in a modest increase in the probability of low VL subsequently. However, several factors mitigate this conclusion. First, this historical comparison might be subject to other unmeasured confounders. Second, a comparison of median VL at the same time point was not significant (4.02 copies/ml and 4.20 copies/ml in Quest and CASCADE, respectively; P=0.55). Finally, additional analysis suggested that the observed difference in low VL at year three would be consistent with an immediate effect of CART only - a delay of usual VL decline without additional benefit. Conclusions A small but significant proportion of seroconverters have low VL without ART. Transient CART in acute infection might increase the probability of low VL after treatment discontinuation, but such an effect is likely to be modest, and might represent a delay of natural history rather than a long-term therapeutic benefit.