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Excessive weight gain associated with integrase strand transfer inhibitor (InSTI) antiretrovirals is an emerging issue; however, the metabolic consequences of this effect have not been established. Our objective was to evaluate for InSTI-emergent weight gain and potential associated type 2 diabetes mellitus (T2DM) among a diverse HIV patient cohort. For this retrospective cohort study, we obtained clinical warehouse data for HIV+ patients between fiscal years 2007–17. We compared patients initiated on an InSTI with those started on an alternate regimen. Our primary outcome was percentage weight change from baseline to 24 months postinitiation using the linear mixed-effects model fit by restricted maximum likelihood. Our secondary outcome was incident T2DM as defined by a new prescription for antihyperglycemic medication within 18 months after antiretroviral therapy (ART) start. Diabetes-free survival was estimated using the Kaplan–Meier method, log-rank test, and Cox proportional-hazards model. The cohort included 1,235 individuals initiating ART, 136 (11.0%) with an InSTI. InSTI use in women was significantly associated with greater weight gain compared with non-InSTIs (11.0%, 95% confidence interval, CI: 5.22 to 16.8, p

Background The factors associated with severe acute respiratory coronavirus 2 (SARS-CoV-2) reinfection remain poorly defined. Methods We identified patients with SARS-CoV-2 infection and at least 1 repeat reverse transcription polymerase chain reaction result a minimum of 90 days after the initial positive test and before 21 January 2021. Those with a repeat positive test were deemed to have reinfection (n = 75), and those with only negative tests were classified as convalescents (n = 1594). Demographics, coronavirus disease 2019 (COVID-19) severity, and treatment histories were obtained from the Boston Medical Center electronic medical record. Humoral responses were analyzed using SARS-CoV-2–specific enzyme-linked immunosorbent assays and pseudovirus neutralizations in a subset of reinfection (n = 16) and convalescent samples (n = 32). Univariate, multivariate, and time to event analyses were used to identify associations. Results Individuals with reinfection had more frequent testing at shorter intervals compared with the convalescents. Unstable housing was associated with more than 2-fold greater chance of reinfection. Preexisting comorbidities and COVID-19 severity after the initial infection were not associated with reinfection. SARS-CoV-2 immunoglobulin G levels and pseudovirus neutralization were not different within the early weeks after primary infection and at a timepoint at least 90 days later in the 2 groups. In the convalescents, but not in those with reinfection, the late as compared with early humoral responses were significantly higher. Conclusions Reinfection associates with unstable housing, which is likely a marker for virus exposure, and reinfection occurs in the presence of SARS-CoV-2 antibodies., SARS-CoV-2 reinfection occurred at greater frequency among individuals with housing instability, and it did not associate with preexisting comorbidities or COVID-19 severity after first infection. Antibodies were detectable among the subset of individuals with documented reinfection examined in this study.

BACKGROUND: Mycobacterium tuberculosis (TB) infection induces systemic inflammation that could impact HIV-1 persistence. SETTING: HIV-1–seropositive individuals either with or without pulmonary TB disease were recruited in Kampala, Uganda. METHODS: Plasma cytokines, HIV-1 DNA, and cell-associated (ca)-RNA were compared among those coinfected with TB (cases) to those without TB (controls). TB-coinfected cases and controls were compared at presentation (n = 15 and n = 16, respectively) and at around 6 months after HIV-1 treatment initiation among those who had achieved virologic suppression (n = 6 and n = 8, respectively). At follow-up, the TB-coinfected cases had also finished TB treatment. RESULTS: Before treatment, the TB-coinfected cases as compared to the controls had higher levels of soluble(s)-CD163 (P = 0.0002) and interleukin-6 (P = 0.006) but lower levels of macrophage chemoattractant protein-1 (P = 0.04). After treatment, the TB-coinfected cases as compared to controls still had higher plasma s-CD163 levels (P = 0007). Controls as compared to the coinfected cases had higher ca-RNA per DNA template both at baseline (P = 0.03) and at follow-up (P = 0.07). Levels of ca-RNA per DNA copy at follow-up showed a negative correlation with baseline plasma s-CD163 (P = 0.008) and interleukin-6 (P = 0.05) levels. CONCLUSIONS: TB disease is associated with inflammation and decreased HIV-1 RNA expression relative to the number of infected cells, both before and after viral suppression. Infections present before antiretroviral initiation impact HIV-1 latency.

Detection of diverse respiratory viruses in Boston was approximately 80% lower after practices were instituted to limit coronavirus disease 2019 (COVID-19) spread compared with the same time period during the previous 5 years. Continuing the strategies that lower COVID-19 dissemination may be useful in decreasing the incidence of other viral respiratory infections.

Background The effectiveness of interleukin-6 inhibitors (IL-6i) in ameliorating coronavirus disease 2019 (COVID-19) remains uncertain. Methods We analyzed data for patients aged ≥18 years admitted with a positive severe acute respiratory syndrome coronavirus 2 polymerase chain reaction test at 4 safety-net hospital systems with diverse populations and high rates of medical comorbidities in 3 US regions. We used inverse probability of treatment weighting via machine learning for confounding adjustment by demographics, comorbidities, and disease severity markers. We estimated the average treatment effect, the odds of IL-6i effect on in-hospital mortality from COVID-19, using a logistic marginal structural model. Results Of 516 patients, 104 (20.1%) received IL-6i. Estimate of the average treatment effect adjusted for confounders suggested a 37% reduction in odds of in-hospital mortality in those who received IL-6i compared with those who did not, although the confidence interval included the null value of 1 (odds ratio = 0.63; 95% confidence interval, .29–1.38). A sensitivity analysis suggested that potential unmeasured confounding would require a minimum odds ratio of 2.55 to nullify our estimated IL-6i effect size. Conclusions Despite low precision, our findings suggested a relatively large effect size of IL-6i in reducing the odds of COVID-19–related in-hospital mortality.

Objective The aim of this observational study was to determine the optimal timing of interleukin-6 receptor inhibitor (IL6ri) administration for coronavirus disease 2019 (COVID-19). Methods Patients with COVID-19 were given an IL6ri (sarilumab or tocilizumab) based on iteratively reviewed guidelines. IL6ri were initially reserved for critically ill patients, but after review, treatment was liberalized to patients with lower oxygen requirements. Patients were divided into two groups: those requiring ≤45% fraction of inspired oxygen (FiO2) (termed stage IIB) and those requiring >45% FiO2 (termed stage III) at the time of IL6ri administration. The main outcomes were all-cause mortality, discharge alive from hospital, and extubation. Results A total of 255 COVID-19 patients were treated with IL6ri (149 stage IIB and 106 stage III). Patients treated in stage IIB had lower mortality than those treated in stage III (adjusted hazard ratio (aHR) 0.24, 95% confidence interval (CI) 0.08–0.74). Overall, 218 (85.5%) patients were discharged alive. Patients treated in stage IIB were more likely to be discharged (aHR 1.43, 95% CI 1.06–1.93) and were less likely to be intubated (aHR 0.43, 95% CI 0.24–0.79). Conclusions IL6ri administration prior to >45% FiO2 requirement was associated with improved COVID-19 outcomes. This can guide clinical management pending results from randomized controlled trials.

Individuals infected with human immunodeficiency virus (HIV) 1 have increased inflammation, which has been associated with age-associated diseases. Plasma markers, cell-associated virus levels, and ability to stimulate RNA transcription in latently infected cell lines was examined in younger and older HIV-1–infected individuals with suppressed virus. Cell-associated RNA, but not intact provirus level, had positive correlation with plasma D-dimer levels. Compared with the younger group, the older group had higher D-dimer levels and a trend toward more cell-associated RNA but similar levels of intact proviruses. Even though all measured inflammatory markers were relatively higher in the older group, this greater inflammation did not induce more HIV-1 transcription in latently infected cell lines. Inflammation and HIV-1 RNA expression increase with age despite similar levels of intact infectious HIV DNA. While plasma inflammation is correlated with HIV-1 RNA expression in peripheral blood mononuclear cells, it does not induce HIV-1 transcription in latently infected cell lines.

Objectives Patients with Covid-19 and obesity have worse clinical outcomes which may be driven by increased inflammation. This study aimed to characterize the association between clinical outcomes in patients with obesity and inflammatory markers. Methods We analyzed data for patients aged ≥18 years admitted with a positive SARS-CoV-2 PCR test. We used multivariate logistic regression to determine the association between BMI and intensive care unit (ICU) transfer and all-cause mortality. Inflammatory markers (C-reactive protein [CRP], lactate dehydrogenase [LDH], ferritin, and D-dimer) were compared between patients with and without obesity (body mass index [BMI] ≥30 kg/m2). Results Of 791 patients with Covid-19, 361 (45.6%) had obesity. In multivariate analyses, BMI ≥35 was associated with a higher odds of ICU transfer (adjusted odds ratio [aOR] 2.388 (95% confidence interval [CI]: 1.074–5.310) and hospital mortality (aOR = 4.3, 95% CI: 1.69–10.82). Compared to those with BMI Conclusions Patients with obesity were more likely to have poor outcomes even without increased inflammation.

Background Excessive weight gain associated with integrase strand transfer inhibitor (InSTI) antiretrovirals is an emerging issue in the current antiretroviral treatment (ART) era. Despite the known association between excess weight and impaired glucose tolerance in the general population, the metabolic implications of InSTI-associated weight gain have not been established. The objective of this study was to evaluate the presence of InSTI-associated weight gain amongst a diverse, urban population and to investigate potential risk factors and metabolic implications. Methods We obtained demographic, pharmacy and laboratory data from the hospital clinical data warehouse for ART-naïve adult HIV+ patients at Boston Medical Center between fiscal year (FY) 2007-2017. We compared patients who initiated on an InSTI to those with an alternate regimen (i.e. PI, NNRTI) who remained on their initial regimen for at least 18 months. Individuals with diabetes mellitus (DM) prescription or ICD 9/10 code prior to ART initiation were excluded. Our primary outcome was percent weight change in the first 24 months of ART estimated by linear mixed effects model fit by restricted maximum likelihood. Our secondary outcome was incident DM diagnosis in the 18 months after ART using progression-free survival (PFS). PFS rates were estimated by the Kaplan-Meier method and log-rank test, and Cox proportional-hazards model were determined, all using R v3.6.2. Results Between FY 2007-2017, 139 patients were initiated on InSTIs and 1117 were initiated on alternative anchor regimens. Approximately, one third of the cohort was female and more than 75% were non-white. InSTI use in women was associated with increased weight gain in the first 24 months of ART compared to non-InSTIs (+9.57%, p = 0.002, Figure 1). InSTI use was associated with more incident DM diagnoses in the first 18 months of ART compared to non-InSTI regimens (HR = 3.27, p = 0.014). Figure 1: Percentage weight change from baseline at ART initiation between InSTI and non-InSTI regimens Conclusion Females have higher InSTI-associated weight gain which suggests they may be more susceptible to adverse metabolic issues. InSTI use appears to be associated with an increased incidence of DM diagnoses following ART initiation. Further prospective and controlled studies will be necessary to describe the mechanism of this effect and refine HIV management strategies. Disclosures Archana Asundi, MD, Gilead (Scientific Research Study Investigator)Merck (Scientific Research Study Investigator)ViiV (Scientific Research Study Investigator) Nina H. Lin, MD, Gilead Sciences (Scientific Research Study Investigator)ViiV (Scientific Research Study Investigator)

A limited number of human immunodeficiency virus type 1 (HIV-1) variants initially infect HIV-1–naive individuals. Recent studies imply that this may occur because generally inefficient transcytosis across intact mucosal surfaces could be enhanced for specific viruses with bound antibodies and in the presence of acidic pH. We found that transcytosis of both cell-free and cell-associated viruses with diverse envelopes was significantly decreased in the presence of either antibodies or plasma from chronically infected transmitting partners regardless of pH. Transmitted variants also did not have greater transmigration as compared to chronic-infection strains. Enhanced translocation capacity is unlikely to influence which HIV-1 variant establishes infection.

Background. Metabolic effects following combination antiretroviral therapy (cART) vary by regimen type. Changes in metabolic effects were assessed following cART in the AIDS Clinical Trials Group (ACTG) A5257 study, and correlated with plasma ritonavir trough concentrations (C24). Methods. Treatment-naive adult subjects were randomized to ritonavir-boosted atazanavir or darunavir, or raltegravir-based cART. Changes in lipids and other metabolic outcomes over time were estimated. Differences between arms were estimated with 97.5% confidence intervals and compared using pairwise Student t tests. Associations between ritonavir C24 and lipid changes at week 48 were evaluated via linear regression. Results. Analyses included 1797 subjects with baseline fasting data. Baseline lipid profiles and metabolic syndrome rates (approximately 21%) were similar across arms. Comparable increases occurred in total cholesterol, triglycerides, and low-density lipoprotein cholesterol with the boosted protease inhibitors (PIs); each PI had greater increases relative to raltegravir (all P ≤ .001 at week 96). Metabolic syndrome incident rates by week 96 (approximately 22%) were not different across arms. Ritonavir C24 was not different by arm (P = .89) (median, 69 ng/mL and 74 ng/mL in the atazanavir and darunavir arms, respectively) and were not associated with changes in lipid measures (all P > .1). Conclusions. Raltegravir produced the most favorable lipid profile. Metabolic syndrome rates were high at baseline and increased to the same degree in all arms. Ritonavir C24 was not different in the PI arms and had no relationship with the modest but comparable increases in lipids observed with either atazanavir or darunavir. The long-term clinical significance of the lipid changes noted with the PIs relative to raltegravir deserves further evaluation. Clinical Trials Registration. {"type":"clinical-trial","attrs":{"text":"NCT 00811954","term_id":"NCT00811954"}}NCT 00811954.

All human immunodeficiency virus type 1 (HIV-1)–infected inocula, such as genital secretions, breast milk, and blood, contain both cell-free virus and infected cells. The relative contributions of cell-free and/or cell-associated virus in establishing an infection in a naive host during the different modes of HIV-1 acquisition remains unclear. Studies aim to elucidate the source of the acquired virus because strategies to prevent acquisition may have differential efficacy against the different modes of transmission. In this review, I will detail some of the challenges in identifying the source of the transmitted virus, genotypic and phenotypic differences among cell-free compared with cell-associated HIV-1, and implications on the efficacy for prevention strategies.

It has been postulated that HIV-1 envelope properties, such as shorter and less glycosylated V1-V2 loops commonly observed among non-subtype B early – transmitted viruses, promote utilization of the gut homing integrin α4β7. This property potentially confers an advantage to some HIV-1 variants early after acquisition. We found that replication competent recombinant viruses incorporating HIV-1 subtype A compact and less glycosylated early versus chronic phase V1-V2 loops demonstrated no significant difference in binding to α4β7 high CD8+ T cells or replication in α4β7 high CD4+ T cells. Integrin α4β7 usage does not select for shorter less glycosylated envelopes during transmission.

Background. The long-term impact of allogeneic hematopoietic stem cell transplantation (HSCT) on human immunodeficiency virus type 1 (HIV-1) reservoirs in patients receiving combination antiretroviral therapy (cART) is largely unknown. Methods. We studied the effects of a reduced-intensity conditioning allogeneic HSCT from donors with wildtype–CCR5 + cells on HIV-1 peripheral blood reservoirs in 2 patients heterozygous for the ccr5Δ32 mutation. Indepth analyses of the HIV-1 reservoir size in peripheral blood, coreceptor use, and specific antibody responses were performed on samples obtained before and up to 3.5 years after HSCT receipt. Results. Although HIV-1 DNA was readily detected in peripheral blood mononuclear cells (PBMCs) before and 2–3 months after HSCT receipt, HIV-1 DNA and RNA were undetectable in PBMCs, CD4 + T cells, or plasma up to 21 and 42 months after HSCT. The loss of detectable HIV-1 correlated temporally with full donor chimerism, development of graft-versus-host disease, and decreases in HIV-specific antibody levels. Conclusions. The ability of donor cells to engraft without evidence of ongoing HIV-1 infection suggests that HIV-1 replication may be fully suppressed during cART and does not contribute to maintenance of viral reservoirs in peripheral blood in our patients. HSCTs with wild-type–CCR5 + donor cells can lead to a sustained reduction in the size of the peripheral reservoir of HIV-1.

Objectives: We previously reported vicriviroc (VCV) resistance in an HIV-infected subject and used deep sequencing and clonal analyses to track the evolution of V3 sequence forms over 28 weeks of therapy. Here, we test the contribution of gp120 mutations to CCR5 antagonist resistance and investigate why certain minority V3 variants emerged as the dominant species under drug pressure. Methods: Nineteen site-directed HIV-1 mutants were generated that contained gp120 VCV resistance mutations. Viral sensitivities to VCV, maraviroc, TAK-779, and HGS004 were determined. Results: Three patterns of susceptibilities were observed as follows: sigmoid inhibition curves with 50% inhibitory concentration similar to pretreatment virus [07J-week 0 (W0)], single mutants with decreased 50% inhibitory concentrations compared with 07J-W0, and mutants that contained ≥5 of 7 VCV resistance mutations with flattened inhibition curves and decreased or negative percent maximal inhibition. Substitutions such as S306P, which sensitized virus to CCR5 antagonists when present as single mutations, were not detected in the baseline virus population but were necessary for maximal resistance when incorporated into V3 backbones that included preexisting VCV resistance mutations. Conclusions: CCR5 antagonist resistance was reproduced only when a majority of V3 mutations were present. Minority V3 loop variants may serve as a scaffold upon which additional mutations lead to complete VCV resistance.

Individuals with recent human immunodeficiency virus type 1 (HIV-1) acquisition are likely to be a major source for other new infections because they have a high level of plasma virus, and the circulating virions possess unique properties that are highly suited for transmission. The acute infection period, however, presents a unique "window of opportunity," because there are a limited number of genetic variants. Studies aim to elucidate the nature of the transmitted viruses and understand the mechanisms that inhibit the majority of variants present in the chronically infected partner from establishing a productive infection in the naive host. Greater understanding of these issues may open promising new ways to effectively block HIV-1 transmission.

Background—Newly infected subjects acquire a limited number of human immunodeficiency virus type 1 (HIV-1) variants with specific genotypic and phenotypic features from the array of viruses present in a chronically infected transmitting partner. Methods—We examined HIV-1 envelope sequences from the earliest available serum sample after HIV-1 acquisition in 13 newly infected subjects and from their epidemiologically linked HIV-1– infected heterosexual partner. Samples from both members were collected on the same day in the Rakai Community Cohort Study. Results—Ten couples were infected with subtype D HIV-1, and 3 pairs had subtype A HIV-1. Newly infected subjects acquired a subset of the viruses that were circulating in the transmitting partner; transmitted variants had less diversity and divergence and were more closely related to the ancestral sequences. The majority of signature amino acid differences among donor and recipient sequences were in and immediately following the V3 loop. Envelopes from recipients were significantly shorter and had a lower V3 charge than envelopes from donors, but there was no significant difference in the number of potential N-linked glycosylation sites. Conclusion—A minority subset of HIV-1 variants with signature genotypes is favored for transmission in this population.

Differences in the extent of genetic diversity have been observed in human immunodeficiency virus type-1 (HIV-1) envelope sequences early in infection, and this has been linked to gender and to modifiable exogenous factors such as hormonal contraceptive use and genital tract infections. But it is unclear whether envelope diversity is indicative of diversity in other regions of the viral genome, and thus whether it adequately reflects whether multiple or a single virus initiated the infection. Here we show that six women with homogeneous envelope V1-V3 sequences during primary infection also had homogeneous gag and polymerase (pol) sequences at the same time. On the other hand, six women with multiple envelope sequences had diverse gag and pol genotypes during a similar interval after infection. This suggests that envelope sequences reflect sequence diversity throughout the viral genomes present early in infection and thus provide an indication of whether a single virus or multiple viruses initiated the infection. Analysis of HIV-1 sequences from about 3 years after infection revealed that the level of diversity and diversification was similar between the women in the two groups.

There are multiple subtypes of HIV-1 circulating worldwide, but recently, subtype C has become highly prevalent, particularly in certain geographic regions. It is unclear whether the dominance of subtype C or other subtypes is due to increased fitness of certain subtypes for transmission, or a founder effect in new, rapidly growing epidemics. To examine whether the prevalence of one subtype increases over the course of an expanding epidemic that includes several circulating subtypes, we examined the distribution of HIV-1 subtypes in Kenya from 1986 to 2000. We found no evidence for an increase in the prevalence of subtype C, which remained low throughout this approximately 15-year period. Interestingly, the percentage of subtype D present in the population decreased significantly over that period, with a slight increase in subtype A. Throughout that period, intersubtype recombinant viruses were detected, including at the early stages of the epidemic. This latter finding suggests that reinfection may have occurred in high-risk groups early in the epidemic, leading to intersubtype recombinant viruses that underwent secondary spread.

(See the editorial commentary by Blish, on pages 1336–8.) Circulating viruses in individuals with chronic human immunodeficiency virus (HIV) infection manifest significant viral genetic diversity, which increases throughout the course of disease [1, 2]. This increase in viral diversity has been observed over the course of the worldwide AIDS epidemic [3]. However, the process by which this viral diversity changes over time within a stable population experiencing an ongoing HIV epidemic and the effects that new transmissions have on this process are unclear. In mother-to-child transmission, only a minor subset of the maternal viral population is passed on to the infant [4]. Similar selection of transmitted viruses has been demonstrated in sexual transmission [5, 6]. Following these initial studies, a detailed analysis of acute infections in heterosexuals demonstrated that in the majority of cases only 1 or a limited number of viral strains establish initial infection, after which there is rapid divergence away from these strains as a result of the evolving immune response [7–15]. These findings are supported by analysis of simian immunodeficiency virus (SIV)–infected macaques, in which the initial founder viral strain persisted at a low level after transmission [16, 17]. Taken together, these data suggest that a bottleneck exists at the point of sexual transmission that limits the viral species that can be efficiently transmitted from host to host [18]. In Rakai, Uganda, viral diversity is significantly lower in newly infected individuals than in persons with chronic disease [19]. Furthermore, variants present in newly infected subjects were genetically more closely related to ancestral strains than to viruses circulating in the transmitting partner at the estimated time of transmission [19]. We used data from HIV-discordant couples enrolled in the Rakai Community Cohort Study (RCCS) to explore whether population HIV-1 genetic diversity is constrained because of the bottleneck present during heterosexual transmission.

Background It has been hypothesized that the RV144 immune correlate, V1V2 antibodies, block binding to gut homing receptor, alpha4 beta7, which may limit virus access to gut associated lymphoid tissue. We hypothesized that if alpha4 beta7 binding is important during HIV-1 acquisition, viruses with envelopes isolated from newly infected subjects should have enhanced ability to bind the alpha4 beta7 integrin and/or infect cells with high levels of alpha4 beta7 receptor compared to variants present in the chronically infected transmitting partner.

As HIV-1 evolves over the course of infection, resistance against antiretrovirals may arise in the absence of drug pressure, especially against receptor and fusion blockers because of the extensive changes observed in the envelope glycoprotein. Here we show that viruses from the chronic phase of disease are significantly less sensitive to CCR5 receptor and fusion blockers compared to early infection variants. Differences in susceptibility to CCR5 antagonists were observed in spite of no demonstrable CXCR4 receptor utilization. No significant sensitivity differences were observed to another entry blocker, soluble CD4, or to reverse transcriptase, protease, or integrase inhibitors. Chronic as compared to early phase variants demonstrated greater replication when passaged in the presence of subinhibitory concentrations of fusion but not CCR5 receptor inhibitors. Fusion antagonist resistance, however, emerged from only one chronic phase virus culture. Because sensitivity to receptor and fusion antagonists is correlated with receptor affinity and fusion capacity, respectively, changes that occur in the envelope glycoprotein over the course of infection confer greater ability to use the CCR5 receptor and increased fusion ability. Our in vitro passage studies suggest that these evolving phenotypes increase the likelihood of resistance against fusion but not CCR5 receptor blockers.

Background. Although broadly neutralizing antibodies (bNAbs) have been shown to block a diverse array of cell-free human immunodeficiency type 1 (HIV-1) infections, it remains unclear whether these antibodies exhibit similar potency against mature dendritic cell (mDC)–mediated HIV-1 trans-infection. Methods. Sensitivity to bNAbs targeting HIV-1 envelope surface unit gp120 (VRCO1, PG16, b12, and 2G12) and transmembrane domain gp41 (4E10 and 2F5) was examined for both cell-free and mDC-mediated infections of TZM-bl and CD4 1 T cells. Results. Compared with cell-free infection, mDC-mediated infection was significantly less susceptible to gp120-directed bNAbs for the majority of virus isolates. A b12 antigen-binding fragment blocked both cell-free and mDC-mediated infection with equal efficiency. In contrast, cell-free and mDC-associated viruses were equally sensitive to gp41-directed bNAbs. Anti-gp41 bNAbs bound to the surface of mDCs and localized at the mDC–T cell synaptic junctions in the absence of virus. Conclusions. Anti-gp41 bNAbs have the potential to inhibit mDC-mediated HIV-1 infection because they bind plasma membranes prior to the formation of an infectious synapse, positioning them to neutralize subsequent virus transfer. As opposed to gp120-directed antibodies, anti-gp41 bNAbs might prevent HIV-1 infection if transmission or spread at the initial site of invasion occurs from a DC-associated source.

HIV has been studied extensively over the past 25 years. Insights into the different stages of the virus’ replication cycle and its interaction with host-cell proteins have led to the development of an armamentarium of effective antiretroviral medications. These antiviral drugs have dramatically changed the prognosis for HIV-infected subjects from an inevitable march towards death to a chronic disease with a potentially normal lifespan. Even with these successes, there is a continuing need to provide new drugs, especially those effective against drug-resistant viruses, to devise optimal strategies to prevent adverse events from either immunosuppression or the antiretroviral medications, and to develop treatments aimed at eliminating virus replication in the absence of antiviral drugs. In this review, how these important issues are being addressed will be highlighted, emphasizing clinical implications from some recent basic science studies and demonstrating how they could change the face of HIV therapeutics over the next 5–10 years.

Our previous studies have shown that the majority of African women were infected with multiple HIV-1 genetic variants while in the remaining women only a single viral genotype was detected early in infection. Infection with multiple viral variants was associated with higher plasma HIV-1RNA levels and faster CD4T-cell decline. Socio-behavioral characteristics use of hormonal contraceptives and the presence of sexually transmitted diseases were prospectively assessed at approximately monthly intervals around the time of HIV-1 acquisition in female sex workers in Kenya. We assessed the relationship between these factors and HIV-1 genetic complexity early in infection. One hundred and fifty-six women were included in this analysis of whom 89 had multiple viral genotypes and 67 had a single genotype at primary infection. Women with multiple variants were more likely to have a genital tract infection [odds ratio (OR) 4.7; 95% confidence interval (CI) 1.4–18.1] or to be using hormonal contraceptives (OR 2.7; 95% CI 1.3–5.6) at the time of their infection than those with a single variant. In multivariate analyses these factors were independent predictors of early HIV-1 genetic complexity and the presence of multiple viral variants early in infection remained significantly associated with a higher steady state plasma HIV-1 RNA level. The presence of genital tract infections and hormonal contraceptive use at the time of transmission were associated with the acquisition of multiple HIV-1 variants. (authors)

Background Mucosally acquired human immunodeficiency virus type 1 (HIV-1) infection results from a limited number of variants, and these infecting strains potentially have unique properties, such as increased susceptibility to entry blockers, relative interferon-alpha (IFN-α) resistance, and replication differences in some primary cells. There is no data about the phenotypic properties of HIV-1 envelope variants found early after acquisition among subjects infected through injection drug use (IDU). For the first time, we compared the characteristics of virus envelopes among injection drug users sampled prior to seroconversion (HIV RNA+/Ab-), within 1 year (early), and more than 2 years (chronic) after estimated acquisition. Results Virus envelopes from 7 HIV RNA+/Ab- subjects possessed lower genetic diversity and divergence compared to 7 unrelated individuals sampled during the chronic phase of disease. Replication competent recombinant viruses incorporating the HIV RNA+/Ab- as compared to the chronic phase envelopes were significantly more sensitive to a CCR5 receptor inhibitor and IFN-α and showed a statistical trend toward greater sensitivity to a fusion blocker. The early as compared to chronic infection envelopes also demonstrated a statistical trend or significantly greater sensitivity to CCR5 and fusion inhibitor and IFN- α. The HIV RNA+/Ab- as compared to chronic envelope viruses replicated to a lower extent in mature monocyte derived dendritic cells – CD4+ T cell co-cultures, but there were no significant replication differences in other primary cells among the viruses with envelopes from the 3 different stages of infection. Conclusions Similar to mucosal acquisition, HIV-1 envelope quasispecies present in injection drug users prior to seroconversion have unique phenotypic properties compared to those circulating during the chronic phase of disease. Electronic supplementary material The online version of this article (doi:10.1186/s12977-014-0106-8) contains supplementary material, which is available to authorized users.