Dr. Dave,

Sorry to bother you but I found this article listed and I thought it was significant because (1) how does one know if they fall into the category below and (2) would one as this need treatment? THanks.

Raymos

Breakthrough HIV Infection in Long-term Exposed HIV Negative Individuals

Some individuals remain HIV seronegative despite repeated exposures to the virus, termed exposed seronegatives. In early 1998, researchers initiated a study to identify and characterize HIV-1 infection in long-term seronegative persons who reported repeated unprotected sexual activities with multiple HIV-1-infected partners.

Results

Investigators in Seattle, WA have identified HIV-1 sequences in 12 of 94 exposed seronegative individuals. Of these 12 infected exposed seronegatives, 2 have remained seronegative and healthy with persistent HIV-1 DNA at extraordinarily low levels. However, the other 10 HIV-1-infected exposed seronegatives seroconverted later.

They first analyzed HIV-1 env sequences in 4 of the late seroconverters and 1 exposed seronegatives whose HIV-1-infected, long-term sexual partners were identified. To our surprise, none of the 5 late seroconverters/exposed seronegatives were infected or superinfected by HIV-1 strains from their long-term sexual partners. In fact, env genetic distances between the breakthrough virus in late seroconverters and their partners' virus were significantly higher than those of pairwise distances between each pair of HIV-1 control sequences randomly chosen from GenBank (p < 0.001).

Interestingly, a higher rate of non-synonymous mutations (dN) (p < 0.05), but not synonymous mutations (dS) (p = 0.34), was found between 3 of the 4 late seroconverters who had HIV-1-specific CD8+ responses (CTL) before seroconversion and their long-term partners, as compared with random HIV-1 pairs. In contrast, the dS but not dN was higher in the late seroconverters who had no detectable CTL responses pre-seroconversion. Furthermore, significant difference in dN but not dS was found between late seroconverters and partners HIV-1 sequences corresponding to multiple CTL epitope pools (including Env, Pol, Gag, and Vpr) that were detected pre-seroconversion.

These findings indicate that breakthrough HIV-1 strains in exposed seronegatives/late seroconverters tends to be divergent from those of their long-term sexual partners, suggesting that continued virus exposures might protect partner-like HIV-1, but allow distinct viral strains to infect. Pre-infection CTL responses might play an important role in the positive selection of breakthrough HIV-1 infection in late seroconverters.

Discussion

This study has two intriguing findings. First, very rarely, HIV-1 can be transmitted to an individual but not cause disseminated infection or seroconversion. HIV DNA can be found in these individuals, but not antibody to HIV, indicationg that infection occurred but did not spread sufficiently through the individual to trigger an antibody response.

Secondly, women who are repeatedly exposed toHIV but not infected (exposed seronegatives) may eventually become infected . Interestingly, the virus they become infected with may not be from their long-term partners but rather from a divergent strain from another individual they had been exposed to. This suggests that the women may have developed immunity to their partners HIV but not to a virus type that was different enough to escape the immune response to their partners virus.

Univ. of Washington, Seattle, USA and Fred Hutchinson Cancer Res. Ctr., Seattle, WA

02/11/04

Reference T Zhu and others. Selection of Breakthrough HIV-1 Infection in Long-term Exposed Seronegative Individuals. Abstract 25 (oral). Program and Abstracts of the 11th Conference on Retroviruses and Opportunistic Infections (11th CROI). February 8-12, 2004. San Francisco, CA.

I was at Dr. Zhu's presentation and since have been waiting for the flood of emails to this forum regarding its findings - particularly the possible identification of individuals who may have been infected with HIV and harbor low levels of virus but have not seroconverted or do so but after a profound delay. In my mind while I was in the audience was how all the many worried well (people who after some indiscretion believe they are HIV infected but who repeatedly test negative for the virus) will run wild with this one. Soem things to consider:

First, these are very provocative results that need further study. Second, it is not a new concept that some people exposed REPEATEDLY to HIV may develop some immune responses to HIV suggesting aborted infection. That some of these people may also ultimately become infected but have virus that is controlled to a level that does not provoke the usual antibody responses is not far fetched. Third, it is critical to realize who the subjects were here. These were partners of HIV+ persons, exposed again and again to HIV - not people who had one or two exposures. Lastly, the researchers found that when these individuals did seroconvert, they did so with detectable virus not matching their partner but from another person.

Much more work needs to validate these findings and characterize these indidividuals.

To answer your questions: One would not know if they were like one of these people. If you have had many many encounters (and I mean the real stuff - lots of shared body fluids) with an HIV+ partner you may be in this situation. IF so, then regular HIV antibody testing is a good idea (as it is anyway). There are no data to suggest treating these people with HIV drugs will be a good or bad thing. Again, more research will be needed to address this.

Thanks, DW