Long-term Therapeutic Impact of the Timing of Antiretroviral Therapy in Patients Diagnosed With Primary Human Immunodeficiency Virus Type 1 Infection

Novelli, Sophie; Lécuroux, Camille; Avettand-Fènoël, Véronique; Seng, Rémonie; Essat, Asma; Morlat, Philippe; Viard, Jean‐Paul; Rouzioux, Christine; Meyer, Laurence; Goujard, Cécile

doi:10.1093/cid/cix1068

Cited by 25 publications

(26 citation statements)

References 36 publications

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“…4B to D) (30,(56)(57)(58). Also consistent with the findings of previous studies of the present (20,30) and other (17,18,59) copies HIV DNA/million cells in MAA ϩ versus MAA Ϫ participants, respectively; P ϭ 0.0045; Fig. 4E).…”

Section: Resultssupporting

confidence: 91%

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HIV Subtype and Nef-Mediated Immune Evasion Function Correlate with Viral Reservoir Size in Early-Treated Individuals

Omondi

Chandrarathna

Mujib

et al. 2019

J Virol

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The HIV accessory protein Nef modulates key immune evasion and pathogenic functions, and its encoding gene region exhibits high sequence diversity. Given the recent identification of early HIV-specific adaptive immune responses as novel correlates of HIV reservoir size, we hypothesized that viral factors that facilitate the evasion of such responses—namely, Nef genetic and functional diversity—might also influence reservoir establishment and/or persistence. We isolated baseline plasma HIV RNA-derivednefclones from 30 acute/early-infected individuals who participated in a clinical trial of early combination antiretroviral therapy (cART) (<6 months following infection) and assessed each Nef clone's ability to downregulate CD4 and human leukocyte antigen (HLA) class Iin vitro. We then explored the relationships between baseline clinical, immunological, and virological characteristics and the HIV reservoir size measured 48 weeks following initiation of suppressive cART (where the reservoir size was quantified in terms of the proviral DNA loads as well as the levels of replication-competent HIV in CD4+T cells). Maximal within-host Nef-mediated downregulation of HLA, but not CD4, correlated positively with post-cART proviral DNA levels (Spearman'sR = 0.61,P = 0.0004) and replication-competent reservoir sizes (Spearman'sR = 0.36,P = 0.056) in univariable analyses. Furthermore, the Nef-mediated HLA downregulation function was retained in final multivariable models adjusting for established clinical and immunological correlates of reservoir size. Finally, HIV subtype B-infected persons (n = 25) harbored significantly larger viral reservoirs than non-subtype B-infected persons (2 infected with subtype CRF01_AE and 3 infected with subtype G). Our results highlight a potentially important role of viral factors—in particular, HIV subtype and accessory protein function—in modulating viral reservoir establishment and persistence.IMPORTANCEWhile combination antiretroviral therapies (cART) have transformed HIV infection into a chronic manageable condition, they do not act upon the latent HIV reservoir and are therefore not curative. As HIV cure or remission should be more readily achievable in individuals with smaller HIV reservoirs, achieving a deeper understanding of the clinical, immunological, and virological determinants of reservoir size is critical to eradication efforts. We performed apost hocanalysis of 30 participants of a clinical trial of early cART who had previously been assessed in detail for their clinical, immunological, and reservoir size characteristics. We observed that the HIV subtype and autologous Nef-mediated HLA downregulation function correlated with the viral reservoir size measured approximately 1 year post-cART initiation. Our findings highlight virological characteristics—both genetic and functional—as possible novel determinants of HIV reservoir establishment and persistence.

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Section: Resultssupporting

confidence: 91%

“…It is now well established that early cART initiation limits the latent HIV reservoir size (16)(17)(18)(19)(20) and that the set-point viral load and duration of viral suppression on cART represent additional positive and negative correlates of reservoir size, respectively (21). Immunological factors also play a role.…”

mentioning

confidence: 99%

HIV Subtype and Nef-Mediated Immune Evasion Function Correlate with Viral Reservoir Size in Early-Treated Individuals

Omondi

Chandrarathna

Mujib

et al. 2019

J Virol

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“…We did not observe any sex‐related difference in long‐term levels of total HIV DNA under ART, contrary to two cross‐sectional studies that reported lower levels in women [14,15]. Most of participants of these studies were chronic initiators, whereas ART initiated during AHI is a major determinant of viral reservoir reduction [16,56‐58]. Here, HIV persistence was evaluated by measure of total HIV DNA in peripheral blood.…”

Section: Discussioncontrasting

confidence: 63%

“…Finally, recent reviews have highlighted the lack of data on sex‐related differences in the establishment and size of the viral reservoir [6,12]. Previous studies have described lower total HIV DNA in women than in men in the first months after infection [13] and under long‐term suppressive ART [14‐16] but no study has assessed it longitudinally.…”

Section: Introductionmentioning

confidence: 99%

Enhanced immunovirological response in women compared to men after antiretroviral therapy initiation during acute and early HIV‐1 infection: results from a longitudinal study in the French ANRS Primo cohort

et al. 2020

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Introduction: Previous studies have reported better immunovirological characteristics in women compared with men after HIV seroconversion. We investigated whether differences persisted under long-term antiretroviral therapy (ART) in individuals treated since acute and early HIV-1 infection (AHI). Methods: Data were obtained for 262 women and 1783 men enrolled between 1996 and 2017 in the French multicentre ANRS PRIMO cohort. We modelled the viral response, long-term immune recovery and HIV DNA decay in the 143 women and 1126 men who initiated ART within the first three months of infection. Results: The participants were mostly white. The mean age was 37 years at AHI diagnosis. Pre-ART viral loads were lower in women than men, 5.2 and 5.6 log 10 copies/mL (p = 0.001). After ART initiation, women more rapidly achieved viral suppression than men (adjusted hazard ratio: 1.33, 95% confidence interval 1.09 to 1.69). They also experienced a faster increase in CD4 + T-cell count and CD4:CD8 ratio during the first months of treatment. Sex-related differences in CD4 + T-cell counts were more pronounced with increasing age. This led to a sustained mean difference of 99 to 168 CD4 + T-cells/µL depending on age between women and men at 150 months of ART. Moreover, CD4:CD8 ratio of women was higher than that of men by 0.31, at 150 months of ART. There was no statistically significant difference between sexes for the levels of HIV DNA over time (mean estimate at the last modelling point: 1.9 log 10 copies/10 6 PBMCs after 70 months of ART for both sexes). Conclusions: The high level of immune recovery and decrease in total HIV DNA levels achieved after ART initiation during AHI reinforce the importance of early diagnosis of HIV infection and immediate ART initiation. The immunological benefit of being female increased throughout prolonged ART duration, which may give women additional protection from adverse clinical events and premature ageing.

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“…Given that reservoir establishment begins shortly after infection and continues as long as viral replication remains uncontrolled [11][12][13], timely viremia suppression with combination antiretroviral therapy (ART) should, in theory, limit reservoir complexity. The observation that early ART limits HIV reservoir size in both adult [14][15][16] and pediatric [17][18][19][20] infection supports this; as do the observations that proviral landscapes in elite controllers and early-treated individuals tend to be more homogeneous than viremic controllers and individuals who initiated ART in chronic infection, respectively [5,21,22]. However, the effect of uncontrolled viremia duration on reservoir diversity in individuals who did not initiate early suppressive ART remains unclear.…”

Section: Introductionmentioning

confidence: 73%

Genetic complexity in the replication-competent latent HIV reservoir increases with untreated infection duration in infected youth

Brumme

Sudderuddin

Ziemniak

et al. 2019

Aids

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Objective: Timely initiation of combination antiretroviral therapy (ART) limits latent HIV reservoir size and should also limit reservoir genetic complexity. However, the relationship between these two factors remains unclear, particularly among HIV-infected youth. Design: Retrospective analysis of replication-competent latent HIV clones serially isolated by limiting-dilution culture from resting CD4+ T-cell reservoirs from ART-suppressed, young adult participants of a historic phase I therapeutic vaccine trial (PACTG/IMPAACT-P1059). Methods: Replication-competent latent HIV clones isolated from resting CD4+ T-cells of 4 perinatally-and 10 non-perinatally-infected young adults (average 22 versus 6 years uncontrolled infection, respectively) were sequenced in Pol and Nef. Within-host HIV sequence datasets were characterized with respect to their genetic diversity and inferred immune escape mutation burden. Results: While participants were comparable in terms of sociodemographic and HIV sampling characteristics (e.g. on average, a mean 17 Pol sequences were recovered at 5 timepoints over up to 70 weeks) and the length of ART suppression at study entry (average 3 years), replicationcompetent HIV reservoir size, genetic diversity, immune escape mutation burden and variant complexity were significantly higher among the perinatally-infected participants who experienced longer durations of uncontrolled viremia. Nevertheless, viral sequences inferred to retain *

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Long-term Therapeutic Impact of the Timing of Antiretroviral Therapy in Patients Diagnosed With Primary Human Immunodeficiency Virus Type 1 Infection

Abstract: Antiretroviral therapy initiated during PHI promotes long-term reduction of HIV reservoir size. In patients with sustained virologic suppression, inflammation may be driven by non-HIV-related factors.

Cited by 25 publications

References 36 publications

HIV Subtype and Nef-Mediated Immune Evasion Function Correlate with Viral Reservoir Size in Early-Treated Individuals

HIV Subtype and Nef-Mediated Immune Evasion Function Correlate with Viral Reservoir Size in Early-Treated Individuals

Enhanced immunovirological response in women compared to men after antiretroviral therapy initiation during acute and early HIV‐1 infection: results from a longitudinal study in the French ANRS Primo cohort

Genetic complexity in the replication-competent latent HIV reservoir increases with untreated infection duration in infected youth

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