The HIV-1 latent reservoir is largely sensitive to circulating T cells

Warren, Joanna; Zhou, Shuntai; Xu, Yinyan; Moeser, Matthew; MacMillan, Daniel; Kirchherr, Jennifer; Sung, Jeffrey C.; Roan, Nadia R.; Adimora, Adaora A.; Joseph, Sarah; Kuruc, JoAnn; Margolis, David M.; Archin, Nancie M.; Brumme, Zabrina L.; Swanstrom, Ronald; Goonetilleke, Nilu

doi:10.7554/elife.57246

Cited by 28 publications

(23 citation statements)

References 111 publications

(168 reference statements)

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“…44 This faster rate of clearance could also be due to the lower proportion of cytotoxic T lymphocyte escape mutations in the reservoir of these participants compared with those treated later; 45 although, this factor remains controversial. 46 As reported in our study, levels of integrated HIV DNA declined less rapidly than levels of total HIV DNA and 2-LTR circles, 14,19,47 indicating that unintegrated HIV genomes are more labile, possibly because they are diluted by T-cell proliferation.…”

Section: Discussionsupporting

confidence: 63%

Long-term effects of early antiretroviral initiation on HIV reservoir markers: a longitudinal analysis of the MERLIN clinical study

et al. 2021

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Background Early antiretroviral therapy (ART) initiation (ie, within 3 months of infection) limits establishment of the HIV reservoir. However, the effect of early ART initiation on the long-term dynamics of the pool of infected cells remains unclear.Methods In this longitudinal analysis, we included cisgender men who have sex with men (MSM) and transgender women (aged 18-54 years) at high risk for HIV infection, enrolled in the ongoing longitudinal MERLIN study in Peru between Oct 28, 2014, and Nov 8, 2018. Participants were eligible if they had been infected with HIV less than 90 days before enrolment, and if they had cryopreserved peripheral blood mononuclear cell (PBMC) samples. Participants were stratified into three groups on the basis of whether they initiated ART at 30 days or less (acute group), at 31-90 days (early group), or more than 24 weeks (deferred group) after the estimated date of detectable infection. PBMC samples were collected before ART initiation and longitudinally for up to 4 years on ART. The main outcomes were to establish the size of the HIV reservoir before ART initiation and to assess the effect of the timing of ART initiation on the decay of the HIV reservoir over 4 years follow-up. We quantified viral load, and isolated CD4 cells to quantify total HIV DNA, integrated HIV DNA and 2-long terminal repeat circles. Longitudinal analysis of active and inducible HIV reservoirs were measured by quantifying the frequency of CD4 cells producing multiply-spliced HIV RNA ex vivo and after in-vitro stimulation with a tat/rev induced limiting dilution assay (TILDA). A mixed-effects model from the time of ART initiation was used to measure longitudinal decays in viral loads and each HIV reservoir measure in each of the three groups.Findings We included 56 participants in this analysis, all of whom were MSM: 15 were in the acute group, 19 were in the early group, and 22 were in the deferred group. Participants in all three groups had similar levels of all HIV reservoir markers before ART initiation. All participants, including those in the acute group, had a pool of transcriptionally silent HIV-infected cells before ART initiation, as indicated by a substantial increase in TILDA measures upon stimulation. Longitudinal analysis over 4 years of ART revealed a biphasic decay of all HIV persistence markers, with a rapid initial decline followed by a slower decay in all participants. During the first-phase decay, the half-lives of both total and integrated HIV DNA and TILDA measures were significantly shorter in the acute group than in the early and deferred groups. During the second-phase decay, HIV reservoir markers continued to decline only in participants in the acute group.Interpretation Participants who initiated ART within 30 days or less of HIV infection showed a steeper and more sustained decay in HIV reservoir measures, suggesting long-term benefit of acute ART initiation on reservoir clearance.

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Section: Discussionsupporting

confidence: 63%

Long-term effects of early antiretroviral initiation on HIV reservoir markers: a longitudinal analysis of the MERLIN clinical study

et al. 2021

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“…When % inhibition was then calculated using Equation (1), we observed that all HIVART participants produced a positive (> 0%) virus inhibition (n=14, range: 8.2% to 73.3% inhibition), consistent with our previous reports that HIVART participants maintain functional HIV-specific CD8 T cells over time ( 16 , 23 ) ( Figure 3B ). The level of inhibition in HD was mostly negative (n=21, mean: -13.7%, range: -49.9 to 20.9%), though some participants produced % inhibition > 0%, suggesting false positives or non-specific CD8 T cell mediated virus inhibition ( Figure 3B ).…”

Section: Resultssupporting

confidence: 88%

Reliable Estimation of CD8 T Cell Inhibition of In Vitro HIV-1 Replication

Weideman

Abad-Fernández

et al. 2021

Front. Immunol.

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The HIV-1 viral inhibition assay (VIA) measures CD8 T cell-mediated inhibition of HIV replication in CD4 T cells and is increasingly used for clinical testing of HIV vaccines and immunotherapies. The VIA has multiple sources of variability arising from in vitro HIV infection and co-culture of two T cell populations. Here, we describe multiple modifications to a 7-day VIA protocol, the most impactful being the introduction of independent replicate cultures for both HIV infected-CD4 (HIV-CD4) and HIV-CD4:CD8 T cell cultures. Virus inhibition was quantified using a ratio of weighted averages of p24+ cells in replicate cultures and the corresponding 95% confidence interval. An Excel template is provided to facilitate calculations. Virus inhibition was higher in people living with HIV suppressed on antiretroviral therapy (n=14, mean: 40.0%, median: 43.8%, range: 8.2 to 73.3%; p < 0.0001, two-tailed, exact Mann-Whitney test) compared to HIV-seronegative donors (n = 21, mean: -13.7%, median: -14.4%, range: -49.9 to 20.9%) and was stable over time (n = 6, mean %COV 9.4%, range 0.9 to 17.3%). Cross-sectional data were used to define 8% inhibition as the threshold to confidently detect specific CD8 T cell activity and determine the minimum number of culture replicates and p24+ cells needed to have 90% statistical power to detect this threshold. Last, we note that, in HIV seronegative donors, the addition of CD8 T cells to HIV infected CD4 T cells consistently increased HIV replication, though the level of increase varied markedly between donors. This co-culture effect may contribute to the weak correlations observed between CD8 T cell VIA and other measures of HIV-specific CD8 T cell function.

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“…However, the question at hand pertains to HIV-specific T cell responses that show evidence of being maintained by recent antigen recognition, indicating that they target epitopes that are intact in at least a portion of the reservoir. Further supporting this idea are the previous observations that (a) the fixation of escape mutations leads to the contraction of corresponding T cell responses ( 51 ) and (b) the substantial majority of HIV-specific T cells that remain detectable after years of ART target epitopes for which escape is not fixed in corresponding reservoir viruses ( 52 , 53 ). As with latency, our data do not lead us to contest the idea that the fixation of escape mutations in the reservoir diminishes the overall potential for immune recognition or the value of therapeutic strategies to address either of these limitations.…”

Section: Discussionmentioning

confidence: 55%

HIV-specific T cell responses reflect substantive in vivo interactions with antigen despite long-term therapy

Stevenson¹,

Ward²,

Truong³

et al. 2021

JCI Insight

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Antiretroviral therapies (ARTs) abrogate HIV replication; however, infection persists as long-lived reservoirs of infected cells with integrated proviruses, which reseed replication if ART is interrupted. A central tenet of our current understanding of this persistence is that infected cells are shielded from immune recognition and elimination through a lack of antigen expression from proviruses. Efforts to cure HIV infection have therefore focused on reactivating latent proviruses to enable immune-mediated clearance, but these have yet to succeed in reducing viral reservoirs. Here, we revisited the question of whether HIV reservoirs are predominately immunologically silent from a new angle: by querying the dynamics of HIV-specific T cell responses over long-term ART for evidence of ongoing recognition of HIV-infected cells. In longitudinal assessments, we show that the rates of change in persisting HIV Nef-specific responses, but not responses to other HIV gene products, were associated with residual frequencies of infected cells. These Nef-specific responses were highly stable over time and disproportionately exhibited a cytotoxic, effector functional profile, indicative of recent in vivo recognition of HIV antigens. These results indicate substantial visibility of the HIV-infected cells to T cells on stable ART, presenting both opportunities and challenges for the development of therapeutic approaches to curing infection.

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The HIV-1 latent reservoir is largely sensitive to circulating T cells

Cited by 28 publications

References 111 publications

Long-term effects of early antiretroviral initiation on HIV reservoir markers: a longitudinal analysis of the MERLIN clinical study

Long-term effects of early antiretroviral initiation on HIV reservoir markers: a longitudinal analysis of the MERLIN clinical study

Reliable Estimation of CD8 T Cell Inhibition of In Vitro HIV-1 Replication

HIV-specific T cell responses reflect substantive in vivo interactions with antigen despite long-term therapy

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