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1.
Sci Adv ; 5(9): eaav2045, 2019 09.
Article in English | MEDLINE | ID: mdl-31579817

ABSTRACT

HIV persistence during combination antiretroviral therapy (cART) is the principal obstacle to cure. Mechanisms responsible for persistence remain uncertain; infections may be maintained by persistence and clonal expansion of infected cells or by ongoing replication in anatomic locations with poor antiretroviral penetration. These mechanisms require different strategies for eradication, and determining their contributions to HIV persistence is essential. We used phylogenetic approaches to investigate, at the DNA level, HIV populations in blood, lymphoid, and other infected tissues obtained at colonoscopy or autopsy in individuals who were on cART for 8 to 16 years. We found no evidence of ongoing replication or compartmentalization of HIV; we did detect clonal expansion of infected cells that were present before cART. Long-term persistence, and not ongoing replication, is primarily responsible for maintaining HIV. HIV-infected cells present when cART is initiated represent the only identifiable source of persistence and is the appropriate focus for eradication.


Subject(s)
HIV Infections/virology , HIV/physiology , Virus Replication , Adolescent , Adult , Anti-HIV Agents/pharmacology , Anti-HIV Agents/therapeutic use , Antiretroviral Therapy, Highly Active , Child , Female , HIV/classification , HIV/drug effects , HIV/genetics , HIV Infections/drug therapy , Humans , Male , Organ Specificity , Phylogeny , RNA, Viral , Sequence Analysis, DNA , Virus Replication/drug effects , Young Adult
2.
Science ; 345(6193): 179-83, 2014 Jul 11.
Article in English | MEDLINE | ID: mdl-24968937

ABSTRACT

The persistence of HIV-infected cells in individuals on suppressive combination antiretroviral therapy (cART) presents a major barrier for curing HIV infections. HIV integrates its DNA into many sites in the host genome; we identified 2410 integration sites in peripheral blood lymphocytes of five infected individuals on cART. About 40% of the integrations were in clonally expanded cells. Approximately 50% of the infected cells in one patient were from a single clone, and some clones persisted for many years. There were multiple independent integrations in several genes, including MKL2 and BACH2; many of these integrations were in clonally expanded cells. Our findings show that HIV integration sites can play a critical role in expansion and persistence of HIV-infected cells.


Subject(s)
Basic-Leucine Zipper Transcription Factors/genetics , HIV Infections/virology , HIV/physiology , Transcription Factors/genetics , Virus Integration/genetics , Virus Latency/genetics , Anti-Retroviral Agents/therapeutic use , Clone Cells/virology , DNA, Viral/analysis , DNA, Viral/genetics , DNA, Viral/metabolism , Genome, Human , HIV/genetics , HIV Infections/drug therapy , HIV Infections/genetics , Humans , RNA, Viral/analysis , RNA, Viral/genetics , RNA, Viral/metabolism
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