Blocking Formation of the Stable HIV Reservoir: A New Perspective for HIV-1 Cure

Goonetilleke, Nilu; Clutton, Genevieve; Swanstrom, R.; Joseph, Sarah

doi:10.3389/fimmu.2019.01966

Cited by 24 publications

(37 citation statements)

References 156 publications

(205 reference statements)

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“…Therapies that limit CD4 + T cell memory generation, perhaps through dampening IL-7/IL-7R signaling in the window from the time of ART initiation to when all viral replication is fully suppressed, could limit reservoir formation (54). Such an approach would not eliminate all of the reservoir, as it is clear that latency can be seeded at different points during untreated infection.…”

Section: Discussionmentioning

confidence: 99%

The replication-competent HIV-1 latent reservoir is primarily established near the time of therapy initiation

et al. 2019

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Although antiretroviral therapy (ART) is highly effective at suppressing HIV-1 replication, the virus persists as a latent reservoir in resting CD4+ T cells during therapy. This reservoir forms even when ART is initiated early after infection, but the dynamics of its formation are largely unknown. The viral reservoirs of individuals who initiate ART during chronic infection are generally larger and genetically more diverse than those of individuals who initiate therapy during acute infection, consistent with the hypothesis that the reservoir is formed continuously throughout untreated infection. To determine when viruses enter the latent reservoir, we compared sequences of replication-competent viruses from resting peripheral CD4+ T cells from nine HIV-positive women on therapy to viral sequences circulating in blood collected longitudinally before therapy. We found that, on average, 71% of the unique viruses induced from the post-therapy latent reservoir were most genetically similar to viruses replicating just before ART initiation. This proportion is far greater than would be expected if the reservoir formed continuously and was always long lived. We conclude that ART alters the host environment in a way that allows the formation or stabilization of most of the long-lived latent HIV-1 reservoir, which points to new strategies targeted at limiting the formation of the reservoir around the time of therapy initiation.

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Section: Discussionmentioning

confidence: 99%

The replication-competent HIV-1 latent reservoir is primarily established near the time of therapy initiation

et al. 2019

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“…The HIV reservoir is established early during primary HIV infection [30,31]. However, in the untreated infection, the reservoir seems to turn over rather quickly, and most proviral DNA sequences in peripheral blood mononuclear cells from ART-treated individuals were recently shown to match circulating HIV variants detected shortly before the start of therapy [32][33][34][35]. In most subjects, the HIV DNA load decreases during the first year after ART initiation, but the decay slows down during years 1-4, and the HIV DNA load eventually reaches a plateau [36].…”

Section: Persistence Of Hiv Reservoirs On Artmentioning

confidence: 99%

Differences in HIV Markers between Infected Individuals Treated with Different ART Regimens: Implications for the Persistence of Viral Reservoirs

Darcis¹,

Berkhout

Pasternak

2020

Viruses

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In adherent individuals, antiretroviral therapy (ART) suppresses HIV replication, restores immune function, and prevents the development of AIDS. However, ART is not curative and has to be followed lifelong. Persistence of viral reservoirs forms the major obstacle to an HIV cure. HIV latent reservoirs persist primarily by cell longevity and proliferation, but replenishment by residual virus replication despite ART has been proposed as another potential mechanism of HIV persistence. It is a matter of debate whether different ART regimens are equally potent in suppressing HIV replication. Here, we summarized the current knowledge on the role of ART regimens in HIV persistence, focusing on differences in residual plasma viremia and other virological markers of the HIV reservoir between infected individuals treated with combination ART composed of different antiretroviral drug classes.

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“…Thus, whilst some sporadic activation of these memory CD4+ T cells may occur once viremia is supressed, on average their rate of activation is much slower. It is an exciting prospect that novel therapeutic strategies that combine cART initiation with inhibition of IL-7/IL-7R signalling to limit CD4+ T cell memory maintenance could limit the HIV-1 reservoir and provide a path to a functional cure [40].…”

Section: Discussionmentioning

confidence: 99%

Limited evolution despite years of measurable viremia in a cART-treated seronegative HIV-1 positive individual

Fryer

Raghwani

Marle

et al. 2020

Preprint

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Understanding the role that antibodies play in controlling HIV-1 infection and in the dynamics that underpin the formation of the HIV-1 reservoir are important steps towards combatting this global disease. To address these gaps, we performed whole-genome, deep sequence analysis of longitudinal plasma HIV-1 samples from an individual who failed to develop detectable anti-HIV-1 antibodies for 4 years post infection. These analyses reveal limited evolution despite months of measurable viremia during treatment with cART. We used a mathematical model to simultaneously analyse the viral and evolutionary dynamics of this unique individual. We propose a role for antibodies in reducing viral infectivity and demonstrate how our data are consistent with a theory of rapid activation of latently infected cells prior to effective viral suppression. Our study supports and elucidates a recent finding that although the latent reservoir persists for years once virus is effectively suppressed, prior to suppression, viral strains within the reservoir turn over rapidly. The implications for a cure are significant.

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Blocking Formation of the Stable HIV Reservoir: A New Perspective for HIV-1 Cure

Cited by 24 publications

References 156 publications

The replication-competent HIV-1 latent reservoir is primarily established near the time of therapy initiation

The replication-competent HIV-1 latent reservoir is primarily established near the time of therapy initiation

Differences in HIV Markers between Infected Individuals Treated with Different ART Regimens: Implications for the Persistence of Viral Reservoirs

Limited evolution despite years of measurable viremia in a cART-treated seronegative HIV-1 positive individual

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