Antiretroviral Therapy Initiated Within 6 Months of HIV Infection Is Associated With Lower T-Cell Activation and Smaller HIV Reservoir Size

Jain, Vivek; Hartogensis, Wendy; Bacchetti, Peter; Hunt, Peter W.; Hatano, Hiroyu; Sinclair, Elizabeth; Epling, Lorrie; Lee, Tzong Hae; Busch, Michael P.; McCune, Joseph M.; Pilcher, Christopher D.; Hecht, Frederick M.; Deeks, Steven G.

doi:10.1093/infdis/jit311

Cited by 287 publications

(267 citation statements)

References 43 publications

Supporting

Mentioning

237

Contrasting

Unclassified

Order By: Relevance

“…Similarly, the "Mississippi child," who started ART at 30 h of age, remained virally suppressed for 27 months in the absence of ART (26). Jain et al (27) showed that early ART (within 6 months of infection) was associated with lower levels of cell-associated HIV DNA and RNA as well as lower levels of CD4 and CD8 T-cell activation. Again, the authors suggested timing of ART to be a critical determinant of reservoir size, consistent with prior studies (11,14,15,(28)(29)(30).…”

Section: Discussionmentioning

confidence: 99%

Monitoring Integration over Time Supports a Role for Cytotoxic T Lymphocytes and Ongoing Replication as Determinants of Reservoir Size

Pinzone

Graf

Lynch

et al. 2016

J Virol

Self Cite

View full text Add to dashboard Cite

The dynamics of HIV reservoir accumulation off antiretroviral therapy (ART) is underexplored. Levels of integrated HIV DNA in peripheral blood mononuclear cells (PBMCs) were longitudinally monitored before and after antiviral therapy. HIV integration increased over time in both elite controllers (ECs; n ‫؍‬ 8) and noncontrollers (NCs; n ‫؍‬ 6) before ART, whereas integration remained stable in patients on ART (n ‫؍‬ 4). The median annual fold change was higher in NCs than in ECs and negatively correlated with CD4/CD8 T-cell ratio. Cytotoxic T lymphocyte (CTL) function as assessed by infected CD4 T-cell elimination (ICE) and granzyme B activity did not significantly change over time in ECs, suggesting that the gradual increase in integrated HIV DNA observed in ECs was not a result of progressive loss of immune-mediated control. Also, acutely infected (n ‫؍‬ 7) but not chronically infected (n ‫؍‬ 6) patients exhibited a significant drop in integrated HIV DNA 12 months after ART initiation. In conclusion, in the absence of ART, integrated HIV accumulates over time both in NCs and in ECs, at variable individual rates. Starting ART early in infection leads to a greater drop in integrated HIV DNA than does initiating treatment after years of infection. The increase in integrated HIV DNA over time suggests that early treatment may be of benefit in limiting HIV reservoirs. IMPORTANCEThe establishment of a latent reservoir represents a barrier to cure among HIV-infected individuals. The dynamics of HIV reservoir accumulation over time in patients before antiviral therapy is underexplored, in large part because it is difficult to accurately and reproducibly measure the size of HIV reservoir in this setting. In our study, we compared the dynamics of integrated HIV DNA over time in ECs and NCs before and after ART was initiated. We found that integrated HIV DNA levels progressively increase over time in the absence of ART, but with a higher, albeit variable, rate in NCs compared to ECs. In addition, integrated HIV DNA declines more dramatically when ART is initiated in acute rather than chronic HIV infection, suggesting important differences between acute and chronic infection. Our study highlights the role of HIV replication and CTL control in reservoir accumulation in sanctuary sites and why ART appears to be more effective in acute infection.

show abstract

Section: Discussionmentioning

confidence: 99%

Monitoring Integration over Time Supports a Role for Cytotoxic T Lymphocytes and Ongoing Replication as Determinants of Reservoir Size

Pinzone

Graf

Lynch

et al. 2016

J Virol

Self Cite

View full text Add to dashboard Cite

show abstract

“…Some clinical studies have shown that early ART not only inhibits HIV-1 replication but also limits the size of viral reservoirs. Continued ART with a reduction in HIV-1 reservoirs over time may facilitate HIV-1 eradication strategies Jain et al 2013;Li and Gandhi 2014;Luzuriaga et al 2014).…”

Section: Current Potential Hiv Cure Strategiesmentioning

confidence: 99%

Might dolutegravir be part of a functional cure for HIV?

2016

View full text Add to dashboard Cite

Antiretroviral therapy (ART) has greatly decreased HIV-related morbidity and mortality. However, HIV can establish viral reservoirs that evade both the immune system and ART. Dolutegravir (DTG) is a secondgeneration integrase strand transfer inhibitor (INSTI) related to the first-generation INSTIs raltegravir (RAL) and elvitegravir (EVG). DTG shows a higher genetic barrier to the development of HIV-1 resistance than RAL and EVG. More interestingly, clinical resistance mutations to DTG in treatment-naïve patients have not been observed to date. This review summarizes recent studies on strategies toward a cure for HIV, explores resistance profiles of DTG, and discusses how DTG might help in finding a functional cure for HIV.Key words: dolutegravir, drug resistance, HIV, cure. Résumé :Les traitements antirétroviraux (TAR) ont considérablement réduit la morbidité et la mortalité associées au VIH. Or, le VIH peut établir des réservoirs viraux pour se soustraire au système immunitaire et aux TAR. Le dolutégravir (DTG) est un inhibiteur du transfert de brin par l'intégrase (integrase strand transfer inhibitor, INSTI) de deuxième génération qui s'apparente au raltégravir (RAL) et à l'elvitégravir (EVG), des INSTI de première génération. Comparativement au RAL et à l'EVG, le DTG présente une plus grande barrière génétique au dével-oppement de la résistance chez le VIH. On remarque avec intérêt que des mutations menant à la résistance clinique au DTG chez des patients jamais traités auparavant n'ont pas encore été observées. La présente revue fait la synthèse des études récentes abordant des stratégies visant à éliminer le VIH, explore les profils de résistance au DTG et discute de la possibilité de mettre au point un remède contre le VIH à l'aide du DTG. [Traduit par la Rédaction]

show abstract

“…In virus controllers, central memory T cell populations seemed to maintain near-normal numbers and to be functionally preserved (29,30), indicating that exposure to viral antigen plays a key role in the establishment of a dysfunctional, unresponsive memory T cell population. Also, in patients who are placed on therapy very early after infection, and who maintain a high level of immunological functionality, the latent HIV-1 reservoir seems to be smaller than that of patients placed on ART during the chronic stage of infection, after their CD4 counts had significantly dropped (31).…”

mentioning

confidence: 96%

Stable Phenotypic Changes of the Host T Cells Are Essential to the Long-Term Stability of Latent HIV-1 Infection

Seu

Sabbaj

Duverger

et al. 2015

J Virol

View full text Add to dashboard Cite

The extreme stability of the latent HIV-1 reservoir in the CD4 ؉ memory T cell population prevents viral eradication with current antiretroviral therapy. It has been demonstrated that homeostatic T cell proliferation and clonal expansion of latently infected T cells due to viral integration into specific genes contribute to this extraordinary reservoir stability. Nevertheless, given the constant exposure of the memory T cell population to specific antigen or bystander activation, this reservoir stability seems remarkable, unless it is assumed that latent HIV-1 resides exclusively in memory T cells that recognize rare antigens. Another explanation for the stability of the reservoir could be that the latent HIV-1 reservoir is associated with an unresponsive T cell phenotype. We demonstrate here that host cells of latent HIV-1 infection events were functionally altered in ways that are consistent with the idea of an anergic, unresponsive T cell phenotype. Manipulations that induced or mimicked an anergic T cell state promoted latent HIV-1 infection. Kinome analysis data reflected this altered host cell phenotype at a system-wide level and revealed how the stable kinase activity changes networked to stabilize latent HIV-1 infection. Protein-protein interaction networks generated from kinome data could further be used to guide targeted genetic or pharmacological manipulations that alter the stability of latent HIV-1 infection. In summary, our data demonstrate that stable changes to the signal transduction and transcription factor network of latently HIV-1 infected host cells are essential to the ability of HIV-1 to establish and maintain latent HIV-1 infection status. IMPORTANCEThe extreme stability of the latent HIV-1 reservoir allows the infection to persist for the lifetime of a patient, despite completely suppressive antiretroviral therapy. This extreme reservoir stability is somewhat surprising, since the latently HIV-1 infected CD4؉ memory T cells that form the structural basis of the viral reservoir should be exposed to cognate antigen over time. Antigen exposure would trigger a recall response and should deplete the reservoir, likely over a relatively short period. Our data demonstrate that stable and system-wide phenotypic changes to host cells are a prerequisite for the establishment and maintenance of latent HIV-1 infection events. The changes observed are consistent with an unresponsive, anergy-like T cell phenotype of latently HIV-1 infected host cells. An anergy-like, unresponsive state of the host cells of latent HIV-1 infection events would explain the stability of the HIV-1 reservoir in the face of continuous antigen exposure.

show abstract

Antiretroviral Therapy Initiated Within 6 Months of HIV Infection Is Associated With Lower T-Cell Activation and Smaller HIV Reservoir Size

Cited by 287 publications

References 43 publications

Monitoring Integration over Time Supports a Role for Cytotoxic T Lymphocytes and Ongoing Replication as Determinants of Reservoir Size

Monitoring Integration over Time Supports a Role for Cytotoxic T Lymphocytes and Ongoing Replication as Determinants of Reservoir Size

Might dolutegravir be part of a functional cure for HIV?

Stable Phenotypic Changes of the Host T Cells Are Essential to the Long-Term Stability of Latent HIV-1 Infection

Contact Info

Product

Resources

About