Viral reservoirs in elite controllers of HIV-1 infection: Implications for HIV cure strategies

Woldemeskel, Bezawit A.; Kwaa, Abena K.; Blankson, Joel N.

doi:10.1016/j.ebiom.2020.103118

Cited by 39 publications

(30 citation statements)

References 78 publications

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“…Similarly, the minimal naive infection in ECs may be related to the minimal viral evolution in this cohort as well as lower levels of CCR5 reported in ECs ( 47 , 48 ). Because ECs have predominant CCR5 tropism and lower peak viral loads than CPs ( 49 ), we postulate that the negligible levels of naive infection in ECs derive from absence of infection rather than preferential clearance.…”

Section: Discussionmentioning

confidence: 99%

Naive infection predicts reservoir diversity and is a formidable hurdle to HIV eradication

Pinzone¹,

Weissman²,

Pasternak³

et al. 2021

JCI Insight

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Historically, naive cells have been considered inconsequential to HIV persistence. Here, we compared the contribution of naive and memory cells to the reservoir of individuals with a spectrum of reservoir sizes and variable immunological control. We performed proviral sequencing of ~6000 proviruses from cellular subsets of 5 elite controllers (ECs) off antiretroviral therapy (ART) and 5 chronic progressors (CPs) on ART.The levels of naive infection were barely detectable in ECs and ~300-fold lower compared to CPs. Moreover, the ratio of infected naive to memory cells was significantly lower in ECs.Overall naive infection level increased as reservoir size increased such that naive cells were a major contributor to the intact reservoir of CPs, whose reservoirs were generally very diverse. In contrast, the reservoirs of ECs were dominated by proviral clones. Critically, the fraction of proviral clones increased with cell differentiation, with naive infection predicting reservoir diversity. Longitudinal sequencing revealed that the reservoir of ECs was less dynamic compared to CPs.Naive cells play a critical role in HIV persistence. Their infection level predicts reservoir size and diversity. Moreover, the diminishing diversity of the reservoir as cellular subsets mature suggests that naive T cells repopulate the memory compartment and that direct infection of naive T cells occurs in vivo.

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Section: Discussionmentioning

confidence: 99%

Naive infection predicts reservoir diversity and is a formidable hurdle to HIV eradication

Pinzone¹,

Weissman²,

Pasternak³

et al. 2021

JCI Insight

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“…Briefly, depending on the clinical progression of the disease, there are different groups of LTNP HIV + individuals: the elite controllers (LTNP-EC), with HIV-1 RNA plasma levels below the level of detection (less than 50 copies of HIV-1 RNA/mL), viremic controllers (LTNP-VC) with HIV-1 RNA levels equal to or below 2,000 copies/mL, non-controllers (LTNP-NC) with levels above 2,000 copies/mL and viremic nonprogressors (VNP) with more than 10,000 copies/mL and normal levels of CD4 + T lymphocytes (Lambotte et al, 2005;Diop et al, 2006;Deeks and Walker, 2007;Canducci et al, 2009;Grabar et al, 2009;Lajoie et al, 2009;Limou et al, 2009;Okulicz et al, 2009;Casado et al, 2010Casado et al, , 2018Rotger et al, 2010;Zhang et al, 2010;Gurdasani et al, 2014;Cabrera-Rodriguez et al, 2019). Nevertheless, despite being controllers, there is evidence of ongoing viral replication in LTNP-EC (Blankson et al, 2007;Lamine et al, 2007;Dinoso et al, 2008;Migueles et al, 2008;Pereyra et al, 2008Pereyra et al, , 2009Hatano et al, 2009;Julg et al, 2010;Mens et al, 2010;O'Connell et al, 2010;Salgado et al, 2010;Zaunders et al, 2011;Noel et al, 2016;Ali et al, 2018;Casado et al, 2018;Woldemeskel et al, 2020), and this endorses the importance of periodically monitoring these patients. The causes of this viral replication control are diverse and may be due to both host and viral factors, thereby making it difficult to establish a precise cause for the natural control of HIV.…”

Section: Introduction a General Overview Of Hiv: Factors Related To The Control Of The Infection And Pathogenesismentioning

confidence: 99%

The Interplay of HIV and Autophagy in Early Infection

et al. 2021

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HIV/AIDS is still a global threat despite the notable efforts made by the scientific and health communities to understand viral infection, to design new drugs or to improve existing ones, as well as to develop advanced therapies and vaccine designs for functional cure and viral eradication. The identification and analysis of HIV-1 positive individuals that naturally control viral replication in the absence of antiretroviral treatment has provided clues about cellular processes that could interact with viral proteins and RNA and define subsequent viral replication and clinical progression. This is the case of autophagy, a degradative process that not only maintains cell homeostasis by recycling misfolded/old cellular elements to obtain nutrients, but is also relevant in the innate and adaptive immunity against viruses, such as HIV-1. Several studies suggest that early steps of HIV-1 infection, such as virus binding to CD4 or membrane fusion, allow the virus to modulate autophagy pathways preparing cells to be permissive for viral infection. Confirming this interplay, strategies based on autophagy modulation are able to inhibit early steps of HIV-1 infection. Moreover, autophagy dysregulation in late steps of the HIV-1 replication cycle may promote autophagic cell-death of CD4+ T cells or control of HIV-1 latency, likely contributing to disease progression and HIV persistence in infected individuals. In this scenario, understanding the molecular mechanisms underlying HIV/autophagy interplay may contribute to the development of new strategies to control HIV-1 replication. Therefore, the aim of this review is to summarize the knowledge of the interplay between autophagy and the early events of HIV-1 infection, and how autophagy modulation could impair or benefit HIV-1 infection and persistence, impacting viral pathogenesis, immune control of viral replication, and clinical progression of HIV-1 infected patients.

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“…The proposed excision of latently infected HIV cells in a second person with HIV infection offers renewed optimism towards a cure that would usher an end to the AIDS crisis (1,2). Although great strides have been undertaken, the cellular responses associated with sustaining persistence versus viral eradication remain poorly understood (3)(4)(5).…”

Section: Introductionmentioning

confidence: 99%

Diminished Peripheral CD29hi Cytotoxic CD4+ T Cells Are Associated With Deleterious Effects During SIV Infection

et al. 2021

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Cytotoxic CD4+ T cells (CD4+ CTLs) limit HIV pathogenesis, as evidenced in elite controllers (a subset of individuals who suppress the virus without the need for therapy). CD4+ CTLs have also been shown to kill HIV-infected macrophages. However, little is known about their contribution towards HIV persistence, how they are affected following exposure to immune modulators like morphine, and what factors maintain their frequencies and function. Further, the lack of robust markers to identify CD4+ CTLs in various animal models limits understanding of their role in HIV pathogenesis. We utilized various PBMC samples obtained from SIV infected and cART treated rhesus macaques exposed to morphine or saline and subjected to flow cytometry evaluations. Thereafter, we compared and correlated the expression of CD4+ CTL-specific markers to viral load and viral reservoir estimations in total CD4+ T cells. We found that CD29 could be reliably used as a marker to identify CD4+ CTLs in rhesus macaques since CD29hi CD4+ T cells secrete higher cytotoxic and proinflammatory cytokines following PMA/ionomycin or gag stimulation. In addition, this immune cell subset was depleted during untreated SIV infection. Strikingly, we also observed that early initiation of cART reconstitutes depleted CD29hi CD4+ T cells and restores their function. Furthermore, we noted that morphine exposure reduced the secretion of proinflammatory cytokines/cytotoxic molecules in CD29hi CD4+ T cells. Lastly, increased functionality of CD29hi CD4+ T cells as depicted by elevated levels of either IL-21 or granzyme B hi T Bet+ gag specific responses were linked to limiting the size of the replication-competent reservoir during cART treatment. Collectively, our data suggest that CD4+ CTLs are crucial in limiting SIV pathogenesis and persistence.

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Viral reservoirs in elite controllers of HIV-1 infection: Implications for HIV cure strategies

Cited by 39 publications

References 78 publications

Naive infection predicts reservoir diversity and is a formidable hurdle to HIV eradication

Naive infection predicts reservoir diversity and is a formidable hurdle to HIV eradication

The Interplay of HIV and Autophagy in Early Infection

Diminished Peripheral CD29hi Cytotoxic CD4+ T Cells Are Associated With Deleterious Effects During SIV Infection

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