Impact of Analytical Treatment Interruption on Burden and Diversification of HIV Peripheral Reservoir: A Pilot Study

Background: If analytical antiretroviral-treatment (ART) interruption (ATI) might significantly impact quantitative or qualitative peripheral-total HIV-DNA is still debated. Methods: Six chronically HIV-1 infected patients enrolled in APACHE-study were analysed for peripheral-total HIV-DNA and residual viremia, major-resistance-mutations (MRMs) and C2-V3-C3 evolution at pre-ATI (T1), during ATI (T2) and at achievement of virological success after ART-resumption (post-ATI, T3). These data were obtained at three comparable time-points in five chronically HIV-1 infected patients on suppressive ART for ≥1 year, enrolled in MODAt-study. Results: At T1, APACHE and MODAt individuals had similar peripheral-total HIV-DNA and residual viremia (p = 0.792 and 0.662, respectively), and no significant changes for these parameters were observed between T1 and T3 in both groups. At T1, 4/6 APACHE and 2/5 MODAt carried HIV-DNA MRMs. MRMs disappeared at T3 in 3/4 APACHE. All disappearing MRMs were characterized by T1 intra-patient prevalence <80%, and mainly occurred in APOBEC3-related sites. All MRMs persisted over-time in the 2 MODAt. C2-V3-C3 genetic-distance significantly changed from T1 to T3 in APACHE individuals (+0.36[0.11–0.41], p = 0.04), while no significant changes were found in MODAt. Accordingly, maximum likelihood trees (bootstrap > 70%) and genealogical sorting indices (GSI > 0.50 with p-value < 0.05) showed that T1 C2-V3-C3 DNA sequences were distinct from T2 and T3 viruses in 4/6 APACHE. Virus populations at all three time-points were highly interspersed in MODAt. Conclusions: This pilot study indicates that short ATI does not alter peripheral-total HIV-DNA burden and residual viremia, but in some cases could cause a genetic diversification of peripheral viral reservoir in term of both MRMs rearrangement and viral evolution.

Association of Male Sex and Obesity With Residual Plasma Human Immunodeficiency Virus 1 Viremia in Persons on Long-Term Antiretroviral Therapy

Background Although adipose tissue has been proposed to harbor part of the human immunodeficiency virus 1 (HIV-1) reservoir, the influence of host characteristics, including sex and body mass index (BMI), on measures of HIV-1 persistence during antiretroviral therapy (ART) are incompletely understood. Methods We evaluated age, sex, BMI, waist circumference, years on ART, pre-ART HIV-1 RNA, pre-ART CD4+ T-cell count, and initial ART regimen with measures of HIV-1 persistence in blood (residual viremia, cellular HIV-1 DNA and RNA) in a cohort of 295 individuals with well-documented long-term virologic suppression (HIV-1 RNA &lt;50 copies/mL) on ART (AIDS Clinical Trials Group study A5321). Results Men were more likely than women to have detectable plasma HIV-1 RNA by single-copy assay (52% vs 29%; P = .003), and the proportion of participants with detectable residual viremia increased in a stepwise fashion by BMI category (normal weight or underweight, 38%; overweight, 50%; and obese, 55%). ART regimen type was not associated with measures of HIV-1 persistence after controlling for ART duration. Conclusions Sex and obesity are independently associated with residual viremia in people on long-term ART. Additional studies to confirm these relationships and to define the mechanisms by which sex and obesity affect HIV-1 persistence are needed to inform HIV-1 cure strategies.

Characterizing the Latent HIV-1 Reservoir in Patients with Viremia Suppressed on cART: Progress, Challenges, and Opportunities

Modern combination antiretroviral therapy (cART) can bring HIV-1 in blood plasma to level undetectable by standard tests, prevent the onset of acquired immune deficiency syndrome (AIDS), and allow a near-normal life expectancy for HIV-infected individuals. Unfortunately, cART is not curative, as within a few weeks of treatment cessation, HIV viremia in most patients rebounds to pre-cART levels. The primary source of this rebound, and the principal barrier to a cure, is the highly stable reservoir of latent yet replication-competent HIV-1 proviruses integrated into the genomic DNA of resting memory CD4+ T cells. In this review, prevailing models for how the latent reservoir is established and maintained, residual viremia and viremic rebound upon withdrawal of cART, and the types and characteristics of cells harboring latent HIV-1 will be discussed. Selected technologies currently being used to advance our understanding of HIV latency will also be presented, as will a perspective on which areas of advancement are most essential for producing the next generation of HIV-1 therapeutics.

Detectability of HIV Residual Viremia despite Therapy Is Highly Associated with Treatment with a Protease Inhibitor-Based Combination Antiretroviral Therapy

ABSTRACT HIV persistence despite therapy contributes to chronic immune activation and inflammation, increasing the risk of aging-associated events in HIV-infected individuals. We sought here to better understand the complex link between clinical and treatment features and HIV persistence despite therapy. A total of 11,045 samples from 1,160 individuals under combination antiretroviral therapy (cART) with an unquantifiable viral load (VL; limit of quantification, 20 copies/ml) were categorized as detectable or undetectable depending on the detection of a PCR signal using a commercially available assay. Generalized estimating equation (GEE) regression was used to model viral load detectability and to assess the determinants of residual viremia (RV; VL detected below 20 copies/ml) despite therapy. A high VL zenith was associated with a higher probability to have a detectable viremia under cART. Conversely, the probability to have a detectable viral load below 20 copies/ml decreased with time under therapy. Of therapy regimens, protease inhibitor (PI)-based cART was associated with a significantly higher probability of detectable RV compared to nonnucleoside transcriptase inhibitor- or integrase inhibitor-based cART. We found that a PI-based treatment regimen is highly associated with an increased frequency of RV, supporting previous evidence suggesting that PI-based cART regimens could favor ongoing viral replication in some individuals.

Antiretroviral Therapy Reduces T-cell Activation and Immune Exhaustion Markers in Human Immunodeficiency Virus Controllers

Background Despite low plasma human immunodeficiency virus (HIV) RNA, HIV controllers have evidence of viral replication and elevated inflammation. We assessed the effect of antiretroviral therapy (ART) on HIV suppression, immune activation, and quality of life (QoL). Methods A5308 was a prospective, open-label study of rilpivirine/emtricitabine/tenofovir disoproxil fumarate in ART-naive HIV controllers (N = 35), defined as having HIV RNA &lt;500 copies/mL for ≥12 months. The primary outcome measured change in %CD38+HLA-DR+ CD8+ T cells. Residual plasma viremia was measured using the integrase single-copy assay. QoL was measured using the EQ-5D questionnaire. Outcomes were evaluated using repeated measures general estimating equations models. Results Before ART, HIV controllers with undetectable residual viremia &lt;0.6 HIV-1 RNA copies/mL had higher CD4+ counts and lower levels of T-cell activation than those with detectable residual viremia. ART use was effective in further increasing the proportion of individuals with undetectable residual viremia (pre-ART vs after 24–48 weeks of ART: 19% vs 94%, P &lt; .001). Significant declines were observed in the %CD38+HLA-DR+CD8+ T cells at 24–48 (−4.0%, P = .001) and 72–96 (−7.2%, P &lt; .001) weeks after ART initiation. ART use resulted in decreases of several cellular markers of immune exhaustion and in a modest but significant improvement in self-reported QoL. There were no significant changes in CD4+ counts or HIV DNA. Conclusions ART in HIV controllers reduces T-cell activation and improves markers of immune exhaustion. These results support the possible clinical benefits of ART in this population.