Ongoing HIV-1 evolution and reservoir reseeding in two elite controllers with genetically diverse peripheral proviral quasispecies.

BACKGROUND: Elite controllers (EC) are human immunodeficiency virus (HIV)-positive individuals who can maintain low viral loads for extended periods without antiretroviral therapy due to multifactorial and individual characteristics. Most have a small HIV-1 reservoir composed of identical proviral sequences maintained by clonal expansion of infected CD4+ T cells. However, some have a more diverse peripheral blood mononuclear cell (PBMC)-associated HIV-1 reservoir with unique sequences. OBJECTIVES: To understand the turnover dynamics of the PBMC-associated viral quasispecies in ECs with relatively diverse circulating proviral reservoirs. METHODS: We performed single genome amplification of the env gene at three time points during six years in two EC with high intra-host HIV DNA diversity. FINDINGS: Both EC displayed quite diverse PBMCs-associated viral quasispecies (mean env diversity = 1.9-4.1%) across all time-points comprising both identical proviruses that are probably clonally expanded and unique proviruses with evidence of ongoing evolution. HIV-1 env glycosylation pattern suggests that ancestral and evolving proviruses may display different phenotypes of resistance to broadly neutralising antibodies consistent with persistent immune pressure. Evolving viruses may progressively replace the ancestral ones or may remain as minor variants in the circulating proviral population. MAIN CONCLUSIONS: These findings support that the high intra-host HIV-1 diversity of some EC resulted from long-term persistence of archival proviruses combined with the continuous reservoir's reseeding and low, but measurable, viral evolution despite undetectable viremia.

Ongoing HIV-1 evolution and reservoir reseeding in two elite controllers with genetically diverse peripheral proviral quasispecies

BACKGROUND Elite controllers (EC) are human immunodeficiency virus (HIV)-positive individuals who can maintain low viral loads for extended periods without antiretroviral therapy due to multifactorial and individual characteristics. Most have a small HIV-1 reservoir composed of identical proviral sequences maintained by clonal expansion of infected CD4+ T cells. However, some have a more diverse peripheral blood mononuclear cell (PBMC)-associated HIV-1 reservoir with unique sequences. OBJECTIVES To understand the turnover dynamics of the PBMC-associated viral quasispecies in ECs with relatively diverse circulating proviral reservoirs. METHODS We performed single genome amplification of the env gene at three time points during six years in two EC with high intra-host HIV DNA diversity. FINDINGS Both EC displayed quite diverse PBMCs-associated viral quasispecies (mean env diversity = 1.9-4.1%) across all time-points comprising both identical proviruses that are probably clonally expanded and unique proviruses with evidence of ongoing evolution. HIV-1 env glycosylation pattern suggests that ancestral and evolving proviruses may display different phenotypes of resistance to broadly neutralising antibodies consistent with persistent immune pressure. Evolving viruses may progressively replace the ancestral ones or may remain as minor variants in the circulating proviral population. MAIN CONCLUSIONS These findings support that the high intra-host HIV-1 diversity of some EC resulted from long-term persistence of archival proviruses combined with the continuous reservoir's reseeding and low, but measurable, viral evolution despite undetectable viremia.

Comparative HIV-1 Proviral Dynamics in Two Individuals That Maintained Viral Replication Control with or without Antiretroviral Therapy following Superinfection.

The analysis of the HIV-1 proviral dynamics after superinfection in the context of both natural and antiretroviral therapy (ART)-mediated suppression could yield unique insights into understanding the persistence of viral variants that seeded the infected cells at different times. In this study, we performed a longitudinal analysis of the env diversity of PBMC-associated HIV DNA quasispecies in two HIV controllers (EEC09 and VC32) that were superinfected with subtype F1 viruses several years after primoinfection with subtype B viruses. Patient EEC09 started ART soon after superinfection, while patient VC32 maintained a natural control of virus replication for at least six years following the superinfection. Our analysis revealed no significant temporal changes in the overall proportion of primo-infecting and superinfecting proviral variants over 2-3 years after superinfection in both HIV controllers. Upon the introduction of ART, individual EEC09 displayed no evidence of HIV-infected cell turnover or viral evolution, while subject VC32 displayed some level of HIV-infected cell reseeding and detectable evolution (divergence) of both viral variants. These results confirm that proviral variants that seeded the reservoir at different times throughout infection could persist for long periods under fully suppressive ART or natural viremic control, but the HIV-1 proviral dynamics could be different in both settings.

Infusion Reactions After Receiving the Broadly Neutralizing Antibody VRC01 or Placebo to Reduce HIV-1 Acquisition: Results From the Phase 2b Antibody-Mediated Prevention Randomized Trials.

BACKGROUND: The antibody-mediated prevention (AMP) studies (HVTN 703/HPTN 081 and HVTN 704/HPTN 085) are harmonized phase 2b trials to assess HIV prevention efficacy and safety of intravenous infusion of anti-gp120 broadly neutralizing antibody VRC01. Antibodies for other indications can elicit infusion-related reactions (IRRs), often requiring premedication and limiting their application. We report on AMP study IRRs. METHODS: From 2016 to 2018, 2699 HIV-uninfected, at-risk men and transgender adults in the Americas and Switzerland (704/085) and 1924 at-risk heterosexual women in sub-Saharan Africa (703/081) were randomized 1:1:1 to VRC01 10 mg/kg, 30 mg/kg, or placebo. Participants received infusions every 8 weeks (n = 10/participant) over 72 weeks, with 104 weeks of follow-up. Safety assessments were conducted before and after infusion and at noninfusion visits. A total of 40,674 infusions were administered. RESULTS: Forty-seven participants (1.7%) experienced 49 IRRs in 704/085; 93 (4.8%) experienced 111 IRRs in 703/081 (P < 0.001). IRRs occurred more frequently in VRC01 than placebo recipients in 703/081 (P < 0.001). IRRs were associated with atopic history (P = 0.046) and with younger age (P = 0.023) in 703/081. Four clinical phenotypes of IRRs were observed: urticaria, dyspnea, dyspnea with rash, and "other." Urticaria was most prevalent, occurring in 25 (0.9%) participants in 704/085 and 41 (2.1%) participants in 703/081. Most IRRs occurred with the initial infusion and incidence diminished through the last infusion. All reactions were managed successfully without sequelae. CONCLUSIONS: IRRs in the AMP studies were uncommon, typically mild or moderate, successfully managed at the research clinic, and resolved without sequelae. Analysis is ongoing to explore potential IRR mechanisms.

Possible risk compensation, attitudes, and beliefs among Brazilian individuals potentially eligible for pre-exposure prophylaxis.

Pre-exposure prophylaxis (PrEP) prevents HIV infection among men who have sex with men (MSM) and transgender women (TGW) who are the groups that presents the high incidence risk in Brazil. This cross-sectional secondary analysis describes possible risk compensation, attitudes, and beliefs regarding the use of PrEP among 723 MSM and TGW evaluated in the PrEP Brazil study pre-screening phase. Possible risk compensation was reported by 31.6% individuals. In the multivariate model, factors that increased the likelihood of possible risk compensation were: self-referring as white vs. Black (AOR 2.05; CI 1.09, 3.85), perceiving high likelihood of getting HIV in next 12 months (AOR 1.78; CI 1.23, 2.56), being less afraid of HIV infection if using PrEP (AOR 1.93; CI 1.19, 3.14), feeling liberated to have more partners if using PrEP (AOR 2.93; CI 1.92, 4.49), and believing closest friends would use PrEP (AOR 2.51; CI 1.1, 5.71). We found that possible risk compensation was more common among individuals who presented high-risk perception for HIV infection, probably reflecting they feel at risk and could benefit from PrEP use.

HIV-1 elite controllers present a high frequency of activated regulatory T and Th17 cells.

HIV-1 infection is characterized by generalized deregulation of the immune system, resulting in increased chronic immune activation. However, some individuals called HIV controllers (HICs) present spontaneous control of viral replication and have a more preserved immune system. Among HICs, discordant results have been observed regarding immune activation and the frequency of different T cell subsets, including Treg and Th17 cells. We evaluated T cell immune activation, differentiation and regulatory profiles in two groups of HICs-elite controllers (ECs) and viremic controllers (VCs)-and compared them to those of cART-treated individuals (cART) and HIV-1-negative (HIV-neg) individuals. ECs demonstrated similar levels of activated CD4+ and CD8+ T cells in comparison to HIV-neg, while cART and VCs showed elevated T cell activation. CD4+ T cell subset analyses showed differences only for transitional memory T cell frequency between the EC and HIV-neg groups. However, VC individuals showed higher frequencies of terminally differentiated, naïve, and stem cell memory T cells and lower frequencies of transitional memory and central memory T cells compared to the HIV-neg group. Among CD8+ T cell subsets, ECs presented higher frequencies of stem cell memory T cells, while VCs presented higher frequencies of terminally differentiated T cells compared to the HIV-neg group. HICs showed lower frequencies of total Treg cells compared to the HIV-neg and cART groups. ECs also presented higher frequencies of activated and a lower frequency of resting Treg cells than the HIV-neg and cART groups. Furthermore, we observed a high frequency of Th17 cells in ECs and high Th17/Treg ratios in both HIC groups. Our data showed that ECs had low levels of activated T cells and a high frequency of activated Treg and Th17 cells, which could restrict chronic immune activation and be indicative of a preserved mucosal response in these individuals.