One of the most difficult questions to address regarding HIV transmission is whether virus floating free in plasma (cell-free virus) or contained inside cells (cell-associated virus) plays the primary role in causing infection. The issue has important ramifications for the design of biomedical prevention interventions, because cell-associated HIV may be less susceptible to some approaches than cell-free HIV. Back in February a new journal called Science Translational Medicine published a paper that takes a detailed look at the question in six gay male transmission pairs. Although the sample is very small, the results show that virus found free in seminal plasma of the transmitting partner consistently bore the closest resemblance to the virus found in the newly infected individual. The authors acknowledge that larger studies are needed but also note that currently these results “provide the most compelling experimental confirmation for the hypothesis that that cell-free HIV RNA in seminal plasma, and not cell-associated HIV DNA in seminal cells, is the origin of sexually transmitted virus between MSM.”
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UPDATE 9/29/2010: A letter and response in the September 22 issue of Science Translational Medicine address some errors in the original paper and discuss their implications, abstracts and links are added below. Full text is accessible with free registration to the Science website.
Sci Transl Med 10 February 2010:
Vol. 2, Issue 18, p. 18re1
DOI: 10.1126/scitranslmed.3000447
REPORT
The Origins of Sexually Transmitted HIV Among Men Who Have Sex with Men
David M. Butler1, Wayne Delport1, Sergei L. Kosakovsky Pond1, Malcolm K. Lakdawala1, Pok Man Cheng1, Susan J. Little1, Douglas D. Richman1,2 and Davey M. Smith1,2
1University of California, San Diego, La Jolla, CA 92093, USA.
2Veterans Administration San Diego Healthcare System, San Diego, CA 92161, USA.
Although it is known that most HIV-1 infections worldwide result from exposure to virus in semen, it has not yet been established whether transmitted strains originate as RNA virions in seminal plasma or as integrated proviral DNA in infected seminal leukocytes. We present phylogenetic evidence that among six transmitting pairs of men who have sex with men, blood plasma virus in the recipient is consistently more closely related to the seminal plasma virus in the source. All sequences were subtype B, and the env C2V3 of transmitted variants tended to have higher mean isoelectric points, contain potential N-linked glycosylation sites, and favor CCR5 co-receptor usage. A statistically robust phylogenetically corrected analysis did not detect genetic signatures reliably associated with transmission, but further investigation of larger samples of transmitting pairs holds promise for determining which structural and genetic features of viral genomes are associated with transmission.
Sci Transl Med 22 September 2010: Vol. 2, Issue 50, p. 50le1
DOI: 10.1126/scitranslmed.3001416
LETTER
Comment on "The Origins of Sexually Transmitted HIV Among Men Who Have Sex with Men"
Laura Heath1, Lisa M. Frenkel2,3,4, Brian T. Foley5 and James I. Mullins1,2,6
1Department of Microbiology, University of Washington, Seattle, WA 98195–8070, USA.2Department of Laboratory Medicine, University of Washington, Seattle, WA 98195–8070, USA.3Department of Pediatrics, University of Washington, Seattle, WA 98195–8070, USA.4Seattle Children’s Hospital, Seattle, WA 98101–1304, USA.5Los Alamos National Laboratory, Los Alamos, NM 87545, USA.6Department of Medicine, University of Washington, Seattle, WA 98195–8070, USA.
Whether HIV from seminal cells or free HIV in semen is the origin of transmitted virus has important implications for the design of transmission prevention strategies. We found that a recent claim that HIV originates from seminal plasma and not from seminal cells was erroneous, because it was based on biological specimens that had been mislabeled, mixed-up, or contaminated. The origin of transmitted virus from semen therefore remains an open question.
Sci Transl Med 22 September 2010: Vol. 2, Issue 50, p. 50lr1
DOI: 10.1126/scitranslmed.3001473
LETTER
Response to Comment on "The Origins of Sexually Transmitted HIV Among Men Who Have Sex with Men"
Davey Smith1,2,*†, Wayne Delport1,*, David Butler1, Susan Little1, Douglas Richman1,2 and Sergei Kosakovsky Pond1
1University of California, San Diego, La Jolla, CA 92093, USA.2Veterans Administration San Diego Healthcare System, San Diego, CA 92161, USA.
In this investigation, we evaluated explanations for the unusual degree of genetic diversity in HIV populations within the sampled seminal cell and plasma compartments observed in our previous study. These analyses included clonal sequencing of HIV DNA in peripheral blood mononuclear cells, ultradeep sequencing of HIV RNA in blood plasma, human leukocyte antigen (HLA) haplotyping of previously used samples, and a BLAST screen against both a local and public repository of HIV-1 sequences, and the investigations to determine whether these observations were secondary to contamination or artifact were unsuccessful. As there are very few HIV sequences from seminal cell tissues and transmission pairs described in the literature, future studies that evaluate more transmission pairs with sampling from multiple anatomic compartments and at multiple time points will most likely be required to resolve this controversy.
What has changed since then?
Posted by: Stephen Kiboi | June 20, 2019 at 10:33 AM