An analysis of HIV isolates from 102 individuals very recently infected with HIV shows that in three-quarters of cases, a single virus was the ancestor of all the viruses isolated from that individual, suggesting to the researchers that immune defences against HIV are highly efficient and usually able to prevent infections by swarms of viruses.
On emember of the research group, Professor George Shaw of the University of Alabama at Birmingham, told The Birmingham News: “"The reason [the finding is] important is it says if we're trying to develop a vaccine or microbicide or whatever to prevent infection, the only thing it has to do is prevent the transmission of a single virus," Shaw said. "That should be possible. All you have to do is provide some additional block to what already is an efficient process."
In contrast, other sexually transmitted infections are the consequence of infection by huge numbers of bacteria.
The findings, published in the May 27th edition of the Proceedings of the National Academy of Sciences, lend weight to the reliability of estimates of the low per-contact risk of HIV transmission, say the researchers, and are also important because they should encourage vaccine researchers to focus down on the characteristics of `early founder` viruses that evade immune defences to establish productive infections.
However, the study also found that in half of the men who have sex with men sampled in the study, the viral population was descended from multiple `founder viruses`. At this point, say the researchers, they don’t know whether this is a consequence of a large number of sexual partners in a short period of time (leading to multiple exposures to HIV), and they are investigating the question in other cohorts.
The study examined isolates from 102 individuals with subtype B virus, 54 of whom were regular blood donors who had not identified risk factors for HIV infection. These indviduals were of particular interest because multiple sequential samples were available. The remainder comprised 23 high-risk heterosexuals, 20 men who have sex with men and one injecting drug user.
The researchers sequenced 3499 full-length env genes from 102 individuals (median 25 sequences per subject) and analysed them for diversity.
Since a new generation of virions is produced each day, and dates of infection for study subjects could be confidently indentified in most cases, the researchers were able to model the expected degree of viral diversity that would be expected in a given time period, assuming no pressure from the immune system for viruses to change in order to evade cytotoxic lymphocytes during the early weeks of infection.
They were able to identify 21 isolates that showed greater evidence of diversity than others.
They went on to compare the genetic patterns of the sequences for each study subject, and constructed a phylogenetic tree, a form of ancestral tree which attempts to reconcile the range of differences seen among sequences into a common ancestral, or consensus, gene sequence. The researchers identify this consensus sequence by looking for common gene patterns across all the viruses under study, and by looking for the point at which mutations arise and get passed on to subsequent generations.
The researchers identified 78 study subjects in whom the genetic evidence pointed to a single `founder virus` and 24 in whom infection appeared to have resulted from multiple viruses. They were able to study viral evolution in 10 subjects for whom multiple samples were available at different stages of primary infection, and found that the proportion of identical viral sequences declined in agreement with a mathematical model of viral diversity during primary infection.
The analysis of these longitudinal samples also demonstrated that the virus population continued to be overwhelmingly dominated by the progeny of the founder virus until the development of cytotoxic lymphocyte responses encouraged the development of `escape mutants` at the time viral load declined and full antibody responses became apparent. Escape mutants are viruses that change their envelope protein patterns in order to evade cytotoxic lymphocytes programmed to recognise particular HIV protein patterns.
Research also showed that the founder viruses were all sensitive to broadly neutralising antibodies but showed a high frequency of resistance to antibodies targeting the V3 loop of the viral envelope. `Founder viruses` also showed different sensitivity when compared to viruses from chronically infected individuals, indicating the need for vaccine research to focus on `founder viruses`, the researchers say.
Keele BF et al. Identification and characterization of transmitted and early founder virus envelopes in primary HIV-1infection. PNAS 105 (21): 7552-7557, 2008.