Pathogenesis and Treatment of HIV Infection

National Institute Of Allergy And Infectious Diseases

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Abstract

HIV-1 proviruses persist in the CD4+ T cells of HIV-1-infected individuals despite years of combination antiretroviral therapy (cART) with suppression of HIV-1 RNA levels to <40 copies/mL. Greater than 95% of these proviruses detected in circulating peripheral blood mononuclear cells (PBMCs) are referred to as defective by virtue of not being able to encode replication-competent viruses due to large internal deletions and lethal genetic mutations. As these defective proviruses are unable to encode intact and replication-competent viruses, they have long been thought of as a biologically irrelevant graveyard of viruses with little significance to HIV-1 pathogenesis. Contrary to this notion, we have recently demonstrated that these defective proviruses are not silent, are capable of transcribing novel unspliced forms of HIV-RNA transcripts with competent open reading frames (ORFs), and can be found in the peripheral blood CD4+ T cells and a wide array of tissues in patients at all stages of HIV-1 infection. The persistent production of HIV-1 proteins in the absence of viral replication helps explain persistent immune activation despite HIV-1 levels below detection, and also presents new challenges to HIV-1 eradication. The degree to which residual viral expression across host tissues differs between individuals with controlled versus active viral replication was examined using post-mortem specimens from 13 persons with HIV. Cell-associated HIV RNA was detected in 12 of 13 donors and in 27 of the 30 tissues examined. There were no statistically significant differences between the ‘Active’ group (HIV-RNA detected in peripheral blood at the time of autopsy, n = 5) and the ‘Suppressed’ group (HIV-RNA not detected in peripheral blood at the time of autopsy, n = 8) (Fisher’s exact test, P > 0.10 for all comparisons). No universal tissue hot spots were identified for either HIV-DNA and/or cell-associated HIV-RNA. HIV-1 proviruses with the potential to encode replication-competent viruses were detected in 9 out of 10 donors for whom HIV-1 sequence data were available (Imamichi et al., J Clin Invest, 2025 135(12):e190824. https://doi: 10.1172/JCI190824). This was observed in 4.3%-7.1% of sequences in the ‘Active’ group and 0%–17.4% of sequence in the ‘Suppressed’ group. Intact proviruses were randomly distributed across different tissue sites, with no observed differences between the ‘Active’ and ‘Suppressed’ groups. Approximately 50% of the proviral sequences in both groups were repeatedly detected in single-genome PCR amplicons at their limiting dilutions, indicating that identical HIV sequences appeared across multiple serial dilutions and thus represented clonal expansions. These clonally expanded proviruses were seen in multiple tissues and approximately half of them contained open reading frames, highlighting their potential biologic significance. A combination of an anti-CD4 antibody and the drug lenacapavir was able to suppress HIV-1 in a person with HIV infection with multi-drug resistant virus.