HLA class I protective alleles in an HIV-1-infected subject homozygous for CCR5-Δ32/Δ32
ABSTRACT Homozygosity for a 32bp deletion in CCR5 (CCR5-Δ32/Δ32) is associated with strong resistance against HIV-1 infection. Several HLA types have been associated to improved viral control and/or delayed progression to AIDS. We report a unique HIV-1 infected individual homozygous for CCR5-Δ32/Δ32 and carrier of HLA-A*2402 and HLA-B*5701. In comparison with earlier data and although a replication competent virus has been isolated, the patient presents better immune status, response to treatment and disease evolution, which may be related to the control exerted by HLA class I restricted T cell immunity. Importantly, the accumulation of protective factors does not warrant a complete protection to HIV infection and the subsequent life-long treatment.
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ABSTRACT: There is intense interest in developing curative interventions for HIV. How such a cure will be quantified and defined is not known. We applied a series of measurements of HIV persistence to the study of an HIV-infected adult who has exhibited evidence of cure after allogeneic hematopoietic stem cell transplant from a homozygous CCR5Δ32 donor. Samples from blood, spinal fluid, lymph node, and gut were analyzed in multiple laboratories using different approaches. No HIV DNA or RNA was detected in peripheral blood mononuclear cells (PBMC), spinal fluid, lymph node, or terminal ileum, and no replication-competent virus could be cultured from PBMCs. However, HIV RNA was detected in plasma (2 laboratories) and HIV DNA was detected in the rectum (1 laboratory) at levels considerably lower than those expected in ART-suppressed patients. It was not possible to obtain sequence data from plasma or gut, while an X4 sequence from PBMC did not match the pre-transplant sequence. HIV antibody levels were readily detectable but declined over time; T cell responses were largely absent. The occasional, low-level PCR signals raise the possibility that some HIV nucleic acid might persist, although they could also be false positives. Since HIV levels in well-treated individuals are near the limits of detection of current assays, more sensitive assays need to be developed and validated. The absence of recrudescent HIV replication and waning HIV-specific immune responses five years after withdrawal of treatment provide proof of a clinical cure.PLoS Pathogens 05/2013; 9(5):e1003347. DOI:10.1371/journal.ppat.1003347 · 8.06 Impact Factor
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ABSTRACT: Genome editing using zinc finger nucleases (ZFNs) has been successfully applied to disrupt CCR5 or CXCR4 host factors and inhibit viral entry and infection. Gene therapy using ZFNs to modify the PSIP1 gene, which encodes the lens epithelium-derived growth factor (LEDGF) protein, might restrain an early step of the viral replication cycle at the integration level. ZFNs targeting the PSIP1 gene (ZFNLEDGF) were designed to specifically recognize the sequence after the integrase binding domain (IBD) of the LEDGF/p75 protein. ZFNLEDGF successfully recognized the target region of the PSIP1 gene in TZM-bl cells by heteroduplex formation and DNA sequence analysis. Gene editing induced a frameshift of the coding region and resulted in the abolishment of LEDGF expression at the mRNA and protein levels. Functional assays revealed that infection with the HIV-1 R5 BaL or X4 NL4-3 viral strains was impaired in LEDGF/p75 knockout cells regardless of entry tropism due to a blockade in HIV-1 proviral integration into the host genome. However, residual infection was detected in the LEDGF knockout cells. Indeed, LEDGF knockout restriction was overcome at a high multiplicity of infection, suggesting alternative mechanisms for HIV-1 genome integration rather than through LEDGF/p75. However, the observed residual integration was sensitive to the integrase inhibitor raltegravir. These results demonstrate that the described ZFNLEDGF effectively targets the PSIP1 gene, which is involved in the early steps of the viral replication cycle; thus, ZFNLEDGF may become a potential antiviral agent for restricting HIV-1 integration. Moreover, LEDGF knockout cells represent a potent tool for elucidating the role of HIV integration cofactors in virus replication.Antimicrobial Agents and Chemotherapy 05/2014; 58(8). DOI:10.1128/AAC.02690-14 · 4.45 Impact Factor