Astrocytes as an HIV Reservoir: Mechanism of HIV Infection

Abstract

If we have any hope of achieving a cure for HIV infection, close attention to the cell types capable of getting infected with HIV is necessary. Of these cell types, astrocytes are the most ideal cell type for the formation of such a reservoir. These are long-lived cells with a very low turnover rate and are found in the brain and the gastrointestinal tract. Although astrocytes are evidently resistant to infection of cell-free HIV in vitro, these cells are efficiently infected via cell-tocell contact by which immature HIV virions bud off lymphocytes and have the ability to directly bind to CXCR4, triggering the process of fusion in the absence of CD4. In this review, we closely examine the evidence for HIV infection of astrocytes in the brain and the mechanisms for viral entry and regulation in this cell type, and discuss an approach for controlling this viral reservoir.

Astrocytes sustain long‐term productive HIV‐1 infection without establishment of reactivable viral latency

“…Lastly, a contact with live, apoptotic or necrotic CD4 + T cells did not reverse virus latency. These data are in agreement with previous studies showing no increase in HIV‐1 production by LRAs in persistently infected astrocytes (Chauhan, ; Li et al, ). However, other studies reported some reactivation with bryostatin (Diaz et al, ), JQ1 and various HDAC inhibitors (Gray et al, ; Narasipura et al, ).…”

“…However, our data clearly demonstrate that HFA can be infected by X4‐tropic viruses through their contact with virus‐infected primary human CD4 + T cells. It has been proposed that HIV‐1 infection in astrocytes may be restricted when the infection is very low, a process that can be overcome when the entry barrier is bypassed by VSV‐G pseudotyping (Li et al, ). We recapitulated such a very low infection process by using either m7NDK pseudotypes or a coculture step with virus‐infected CD4 + T cells.…”

“…Although detection of viral DNA might be a consequence of the phagocytosis of HIV‐1‐infected dead cells by astrocytes rather than a true infection, virus‐infected astrocytes are also detected in the simian immunodeficiency virus (SIV) rhesus macaque model (Overholser et al, ). Whether HIV‐1 causes abortive or productive infection of astrocytes is still a matter of debate (Li, Henderson, & Nath, ). Although late HIV‐1 markers such as Gag and Envelope (Env) structural proteins were sometimes detected in infected astrocytes, most in vivo studies demonstrate that only early gene virus products such as Nef are detected (Anderson et al, ; Ranki et al, ; Saito et al, ), thus leading to the concept of a restricted infection with limited or no virus production (Ranki et al, ; Saito et al, ).…”

“…First, endocytosis leads to a very inefficient infection mode due to degradation of most HIV‐1 particles in the endosomal apparatus (Chauhan et al, ; Hao and Lyman, ). Second, a more efficient mode of entry relies on cell‐to‐cell contacts through cocultivation with virus‐infected lymphocytes, which involves a CD4‐independent fusion of immature/budding virions via gp120‐CXCR4 interactions (Li et al, ; Luo and He, ).…”

Synthetic AAV/CRISPR vectors for blocking HIV‐1 expression in persistently infected astrocytes

“…Finally, astrocytes were shown to be capable of transmitting HIV to immune cells by cell‐to‐cell contact in co‐culture experiments (Li et al, ), suggesting that they also contribute to virus spread. For a more in‐depth discussion of the potential of astrocytes to form virus reservoirs and promote neurological damage to the brain and HAND, the reader is referred to selected reviews (Carroll & Brew, ; Gray, Brew, & Churchill, ; Li, Henderson, & Nath, ; Saylor et al, ).…”