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Review
. 2021 Apr 7:12:646447.
doi: 10.3389/fmicb.2021.646447. eCollection 2021.

The Interplay of HIV-1 and Macrophages in Viral Persistence

Chynna M Hendricks  1 , Thaissa Cordeiro  2 , Ana Paula Gomes  2 , Mario Stevenson  2
Affiliations
Review

The Interplay of HIV-1 and Macrophages in Viral Persistence

Chynna M Hendricks et al. Front Microbiol. .

Abstract

HIV-1 has evolved mechanisms to evade host cell immune responses and persist for lifelong infection. Latent cellular reservoirs are responsible for this persistence of HIV-1 despite the powerful effects of highly active antiretroviral therapies (HAART) to control circulating viral load. While cellular reservoirs have been extensively studied, much of these studies have focused on peripheral blood and resting memory CD4+ T cells containing latent HIV-1 provirus; however, efforts to eradicate cellular reservoirs have been stunted by reservoirs found in tissues compartments that are not easily accessible. These tissues contain resting memory CD4+ T cells and tissue resident macrophages, another latent cellular reservoir to HIV-1. Tissue resident macrophages have been associated with HIV-1 infection since the 1980s, and evidence has continued to grow regarding their role in HIV-1 persistence. Specific biological characteristics play a vital role as to why macrophages are latent cellular reservoirs for HIV-1, and in vitro and in vivo studies exhibit how macrophages contribute to viral persistence in individuals and animals on antiretroviral therapies. In this review, we characterize the role and evolutionary advantages of macrophage reservoirs to HIV-1 and their contribution to HIV-1 persistence. In acknowledging the interplay of HIV-1 and macrophages in the host, we identify reasons why current strategies are incapable of eliminating HIV-1 reservoirs and why efforts must focus on eradicating reservoirs to find a future functional cure.

Keywords: HIV; functional cure; host factors; latency; macrophages; reservoirs.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Biological characteristics of macrophage reservoirs. (A) Unpolarized macrophages are stimulated by the local cytokine milieu in different tissue compartments, which causes different macrophage polarization states. Macrophage polarization is a spectrum and reversible. Two extremes are the M1, classically activated or pro-inflammatory, macrophage and the M2, alternatively activated or anti-inflammatory, macrophage, who play different roles within the body. Upon HIV-1 infection, polarization states affect susceptibility of macrophages as well as inhibit viral replication at different points in the HIV-1 replication cycle. (B) Tissue resident macrophages are sustained by self-renewal, and in some tissue, infiltrating macrophages will replenish tissue resident macrophage populations. Both monocyte derived macrophages and tissue resident macrophages are susceptible to HIV-1 infection and can sustain long-term infection with tissue resident macrophages maintaining viral infection for years to decades. (C) Virus containing compartments (VCCs) are formed from the introduction of gag synthesis in the cytosol, promoting the formation of compartments. Viral particles assemble then bud into these VCCs, accumulating over time. Upon cell necrosis or stimulation from the microenvironment, VCCs may release their viral particles.
FIGURE 2
FIGURE 2
HIV-1 has evolved mechanism to evade host immune responses in macrophages. (A) HIV-1 infected macrophages are refractory to the cytopathic effects of viral infection. Infected cells usually undergo apoptosis or cell-mediated killing upon viral infection. HIV-1 upregulates certain factors to evade apoptosis. HIV-1 envelope glycoprotein binds to M-CSF to downregulate TRAIL-receptor and upregulate anti-apoptotic genes. HIV-infected macrophages express higher levels of TREM1, which upregulates and translocates Bim to the mitochondria to downregulate BCL-2 induced apoptosis. Additionally, HIV-infected macrophages have increased telomerase activity, triggering less DNA damage and sustained infection. (B) HIV-1 induces mechanisms to evade IFN responses in infected macrophages through accessory proteins. TREX1 binds to excess HIV DNA during reverse transcription to suppress IFN responses. HIV-1 capsid binds to and removes CPSF6 and cyclophilins to silence downstream innate sensors of IFN pathways. HIV-1 Vif and Vpr bind to TBK1, preventing phosphorylation and downstream IFN induction. HIV-1 Vpr also binds to SLX4 complex with reverse transcribed HIV-1 DNA, like TREX1 to degrade nucleic acids and increase cellular replication stress, leading to G2/M cell cycle arrest and prevent IFN response. (C) CTLs recognize peptide antigens presented by MHC-I and release cytotoxic particles to kill infected cells. HIV-1 infected macrophages are resistant to CTL killing as CTLs require both granzyme B and caspase-3 to efficiently kill HIV-1 infected macrophages unlike CD4+ T cells which only need granzyme B. CTL binding to MHC-I only triggers release of granzyme B, which renders a much slower and less efficient killing of macrophages.
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