HIV Persistence in Adipose Tissue Reservoirs

Abstract

Memory CD4 T cells and macrophages, the major host cells for HIV, accumulate in adipose tissue during HIV/SIV infection of humans and rhesus macaques. Whereas HIV and SIV proviral DNA is detectable in CD4 T cells of multiple fat depots in virtually all infected humans and monkeys examined, viral RNA is less frequently detected, and infected macrophages may be less prevalent in adipose tissue. However, based on viral outgrowth assays, adipose-resident CD4 T cells are latently infected with virus that is replication-competent and infectious. Additionally, adipocytes interact with CD4 T cells and macrophages to promote immune cell activation and inflammation which may be supportive for HIV persistence. Antiviral effector cells, such as CD8 T cells and NK/NKT cells, are abundant in adipose tissue during HIV/SIV infection and typically exceed CD4 T cells, whereas B cells are largely absent from adipose tissue of humans and monkeys. Additionally, CD8 T cells in adipose tissue of HIV patients are activated and have a late differentiated phenotype, with unique TCR clonotypes of less diversity relative to blood CD8 T cells. With respect to the distribution of antiretroviral drugs in adipose tissue, data is limited, but there may be class-specific penetration of fat depots. The trafficking of infected immune cells within adipose tissues is a common event during HIV/SIV infection of humans and monkeys, but the virus may be mostly transcriptionally dormant. Viral replication may occur less in adipose tissue compared to other major reservoirs, such as lymphoid tissue, but replication competence and infectiousness of adipose latent virus are comparable to other tissues. Due to the ubiquitous nature of adipose tissue, inflammatory interactions among adipocytes and CD4 T cells and macrophages, and selective distribution of antiretroviral drugs, the sequestration of infected immune cells within fat depots likely represents a major challenge for cure efforts.

Adipocytes impair efficacy of antiretroviral therapy

“…The results presented here demonstrate that adipocytes have significant impact on ART distribution and activity within AT, which is newly believed to constitute a reservoir for latently infected HIV-/SIV-infected CD4 T cells (Couturier et al, 2015; Damouche et al, 2015; Couturier et al, 2016; Damouche et al, 2017; Hsu et al, 2017; Koethe et al, 2017; Couturier et al, 2018). In particular, these data suggest that adipocytes markedly diminish the antiretroviral effectiveness of NRTIs, particularly tenofovir, which constitutes an important “backbone” component of many antiretroviral regimens and is a first line agent for the treatment of HIV infection.…”

“…They observed that NNRTI concentrations were significantly higher in AT lysates compared to PI concentrations, whereas N(t)RTIs were undetectable. Others and we have recently demonstrated that latently-infected CD4 T cells accumulate in AT and establish replication-competent reservoirs during chronic HIV infection, indicating the need for better understanding of antiretroviral pharmacology in AT (Couturier et al, 2015; Damouche et al, 2015; Couturier et al, 2016; Damouche et al, 2017; Hsu et al, 2017; Koethe et al, 2017; Couturier et al, 2018). …”

Obesity-Associated Alterations of Natural Killer Cells and Immunosurveillance of Cancer

“…Latest data also provided evidence for a decreased NK cell number in mice orally infected with Salmonella Typhimurium, which also may contribute to an impaired susceptibility for infections in obese individuals (174). Interestingly, it has been proposed that selective therapeutic drugs might get trapped in adipose tissue in the treatment of HIV infections and, furthermore, immune cells, including NK cells, could be retained in adipose tissue, blocking their immunosurveillance elsewhere in the body (175).…”

Specific Biological Features of Adipose Tissue, and Their Impact on HIV Persistence

“…Lastly, the discovery of memory T cell accumulation in AT as a means of providing efficient secondary responses against pathogens constituted a major breakthrough; it became clear that AT is an immune partner in both local and systemic immune responses (Han et al, 2017; Figure 5). However, AT is a reservoir for pathogens in various infectious contexts (Nishimura et al, 2000;Neyrolles et al, 2006;Desruisseaux et al, 2007;Dhurandhar, 2011;Nagajyothi et al, 2012;Couturier et al, 2015Couturier et al, , 2016Damouche et al, 2015;Trindade et al, 2016;Beigier-Bompadre et al, 2017;Tanowitz et al, 2017;Couturier and Lewis, 2018;Contreras et al, 2019; Table 2). The detection of various bacterial DNAs in AT also constitutes an argument in favor of the tissue-specific microbiota hypothesis (Burcelin et al, 2013).…”