The Complex Interactions Between HIV-1 and Human Host Cell Genome: From Molecular Mechanisms to Clinical Practice

Abstract

Antiretroviral therapy (ART) has significantly improved the prognosis of human immunodeficiency virus type 1 (HIV-1) infection. Although ART can suppress plasma viremia below detectable levels, it cannot eradicate the HIV-1 DNA (provirus) integrated into the host cell genome. This integration often results in unrepaired DNA damage due to the HIV-1-induced inhibition of DNA repair pathways. Furthermore, HIV-1 infection causes telomere attrition in host chromosomes, a critical factor contributing to CD4+ T cell senescence and apoptosis. HIV-1 proteins can induce DNA damage, block DNA replication, and activate DNA damage responses across various organs. In this review, we explore multiple aspects of the intricate interactions between HIV-1 and the host genome involved in CD4+ T cell depletion, inflammaging, the clonal expansion of infected cells in long-term-treated patients, and viral latency. We discuss the molecular mechanisms of DNA damage that contribute to comorbidities in HIV-1-infected individuals and highlight emerging therapeutic strategies targeting the integrated HIV-1 provirus.

Keywords: CPSF6; DNA damage; HIV-1; HIV-1 therapies; LEDGF/p75; capsid; latency; viral DNA integration; virus–host interaction.

Figure 1

The viral integrase and Ku70 complex recruits Ku80, DNA-PK, and ATM at the integration site. ATM phosphorylates CHK2 and H2AX, two key proteins that initiate activation of the DNA damage checkpoint. CHK2 inhibits CDC25, preventing cell entry into the S and M phases. The phosphorylated form of H2AX is a scaffold that attracts repair factors to DNA damage sites and retains them until the damage is removed.

Figure 2

Schematic representation of the complex interactions between HIV-1 and the host cell genome. The factors that promote virus production are as follows: (i) integration into nuclear speckles; (ii) integration in the same orientation as host genes; and (iii) integration within genes marked by H3K36me3, H3K9ac, or H3K4me3 epigenetic histone modifications. Integration into heterochromatin, in the opposite orientation to host genes, or in genes marked by H3K27 or H3K9 histone epigenetic modifications promotes viral latency. Integration and Vpr can cause DNA damage, which is not repaired due to PI3K/ATM suppression by Vif. Replication pressure caused by HIV-1-induced CD4+ T cell depletion, PI3K/ATM suppression, DNA damage, reduced telomerase levels, and treatment with NRTIs leads to progressive telomere shortening. Telomere shortening is a cause of CD4+ T cell depletion and, together with DNA damage, contributes to inflammaging.

Figure 3

Vpr unwinds double-stranded DNA by converting it into a relaxed form and induces the ubiquitination of histone H2B. This chromatin remodeling promotes the efficient loading of RPA70 that activates the ATR-dependent DDR. In addition, the Vpr-induced unwinding of double-stranded DNA results in the accumulation of negatively supercoiled DNA and covalent complexes of topoisomerase 1 and DNA, which cause DSBs. Vpr promotes the degradation of several DDR proteins, inhibiting double-strand DNA break repair by recruiting the CRL4ADCAF1 ubiquitin ligase complex. Vif blocks the Vpr-directed activation of ATM but not ATR.

Figure 4

CPSF6 plays a predominant role in directing HIV-1 integration into gene-dense regions of euchromatin. Knockout or knockdown of the host factor CPSF6 or treatment with Lenacapavir results in a significant preference for HIV-1 provirus integration into LADs. The repressive chromatin environment of LADs may help maintain the provirus in a silent state.

Figure 5

(A) Long-term ART-treated individuals are characterized by large clones of intact proviruses preferentially integrated in heterochromatin locations. (B) A theoretical model in which long-term treatment with ART including capsid inhibitors could lead to the clonal expansion of CD4+ T cells harboring proviruses integrated into LADs and silenced therein.