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. A series of genome-wide association studies were conducted using stored samples from the ESPRIT, START and SMART clinical trials. Among 4829 subjects there were 132 AIDS-defining events; 136 chronic inflammation-related conditions; 167 bacterial pneumonias; 45 infection-related cancers and 49 herpes-virus related events. Several different HLA-associations were noted among them HLA-DQB1*06:04 and HLA-DRB1*13:02 with AIDS-defining events. In a separate study, baseline levels of hsCRP, D-dimer and IL-6 and single nucleotide polymorphisms were determined for 7768 subjects and analyzed according to ethnic group. Three novel, ethnic-specific loci were identified. These included CATSPERG with D-dimer in Africans and PROX1-AS1 and TRAPPC9 with IL-6 in Africans and admixed Americans. In a separate study , eight-day inpatient directly observed anti-retroviral therapy demonstrated non-adherence as the major cause of virologic failure for 9/20 (45%) of highly treatment-experienced persons with HIV and extensive resistance to anti-retroviral drugs. This was despite high self-reported rates of adherence and avoided unnecessary changes in treatment regimens.