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-infected individuals despite years of combination antiretroviral therapy (cART) with suppression of HIV-1 RNA levels <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 having 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 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 of 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. We observed long-term persistence of multiple, unique, transcriptionally-active "defective" HIV-1 provirus clones (average: 11 yrs., range: 4-20 yrs.) and antibody responses against HIV-1 viral proteins among ART-treated participants. A direct correlation was observed between the magnitude of HIV-1 antibody response and the levels of transcription of "defective" HIV-1 proviruses. Additional correlations were noted between total CD8 + T cell counts and HIV-DNA or cell associated HIV-RNA. These findings suggest a novel interplay between transcription and translation of "defective" HIV-1 proviruses and the persistent immune activation seen in the setting of treated chronic HIV-1 infection.