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Sex Transmission: Defining Mucosal
Immune Factors That Stymie HIV Remains Tough Job
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1st International Workshop on HIV and Women, January 10-11, 2011, Washington, DC
Mark Mascolini
Analyzing research on genital immunology and HIV transmission, Rupert Kaul (University of Toronto) stressed three points [1]:
· The risk of HIV transmission through sex is "low but very variable."
· Mucosal immunology is important: the number and nature of target cells in genital and rectal linings of an HIV-negative partner matter, as do that partner's antimicrobial defenses.
· But defining "protective" mucosal immune factors can be very difficult.
The estimated risk of HIV transmission during sexual intercourse ranges from 0.1% to 3.0% per act of receptive anal intercourse to only 0.09% per mucous membrane exposure. Between these poles lie estimated rates for receptive vaginal intercourse (0.1% to 0.2%), insertive vaginal intercourse (0.03% to 0.09%), insertive anal intercourse (0.06%), and receptive oral sex (fellatio) (0% to 0.04%). Despite these low transmission risks, Kaul noted, UNAIDS estimated that 33.4 million people worldwide carried HIV in 2008, most of them infected sexually.
Kaul proposed that HIV transmission depends on three things: (1) infectious virus in genital or rectal secretions of the infected partner, (2) access to susceptible cells in the exposed mucosa of the uninfected partner, and (3) avoidance of innate antimicrobial defense proteins such as alpha- and beta-defensins, SLPI, RANTES, Trappin-2 (elafin), and cathelicidins. Availability of HIV targets differs at mucosal exposure sites, Kaul noted, and that partly explains why infection via receptive anal intercourse is so much more likely than infection during receptive oral intercourse: The estimated proportion of vulnerable CCR5-expressing cells in the rectosigmoid colon is about 71%, compared with about 15% in tonsil [2].
Several studies offer evidence that genital coinfections favor HIV acquisition. For example, herpes simplex virus type 2 infection has been associated with a 3-fold increase in HIV risk [3]. Bacterial vaginosis may inflate the risk of HIV infection by 60% [4]. Other work implicates trichomoniasis, gonorrhea, and other genital infections.
Given those correlations, why has treatment of sexually transmitted infections failed to slow HIV transmission? The most notable failure of this approach involves acyclovir treatment of HSV-2. To explain that failure, Kaul cited evidence demonstrating the delayed impact of HSV-2 therapy on reducing genital target cells [5]. High levels of CD4 cells, CD8 cells, and dendritic cells persisted at sites of HSV-2 reactivation for months after lesion healing, even among people taking daily acyclovir.
Although research has identified an army of genital immune defenses against HIV (SLPI, Trappin-2, lactoferrin, alpha- and beta-defensins, interferon-alpha, various beta chemokines), Kaul observed, "real-world" immune protection is harder to define. Although most sexual and needlestick exposures do not lead to infection, regular exposure heightens a person's long-term acquisition risk. Researchers in Rakai estimated an average 12% transmission rate in discordant couples over the course of a year [6].
The role of innate inhibitory factors can be complicated, Kaul and collaborators found in a prospective case-control study involving 466 Kenyan sex workers [7]. Researchers banked cervicovaginal lavage samples from HIV-negative women at enrollment and tested them regularly for HIV acquisition. An independent statistician matched each of the 35 women who became infected with four controls who did not acquire HIV. Investigators blinded to HIV outcomes assessed levels of innate immune factors in lavage samples collected at the end of the study.
Cervicovaginal secretions contained high levels of defensins, the cathelicidin LL-37, and SLPI. Secretions from 20% of participants neutralized a subtype A primary HIV isolate, and secretions from 12% neutralized both subtype A and subtype B isolates. But alpha-defensin and LL-37 levels were higher in women with bacterial sexually transmitted infections and were independently associated with increased HIV acquisition in multivariate analysis.
Kaul concluded that studies of purported "protective" immune factors "must be careful to avoid confounding."
References
1. Kaul R. Genital immunology and HIV transmission. 1st International Workshop on HIV and Women. January 10-11, 2011. Washington, DC. Invited lecture.
2. Grivel JC, Elliott J, Lisco A, et al. HIV-1 pathogenesis differs in rectosigmoid and tonsillar tissues infected ex vivo with CCR5- and CXCR4-tropic HIV-1. AIDS. 2007;21:1263-1272.
3. Glynn JR, Biraro S, Weiss HA. Herpes simplex virus type 2: a key role in HIV incidence. AIDS. 2009;23:1595-1598.
4. Atashili J, Poole C, Ndumbe PM, Adimora AA, Smith JS. Bacterial vaginosis and HIV acquisition: a meta-analysis of published studies. AIDS. 2008;22:1493-1501.
5. Zhu J, Hladik F, Woodward A, Klock A, et al. Persistence of HIV-1 receptor-positive cells after HSV-2 reactivation is a potential mechanism for increased HIV-1 acquisition. Nat Med. 2009;15:886-892.
6. Quinn TC, Wawer MJ, Sewankambo N, et al. Viral load and heterosexual transmission of human immunodeficiency virus type 1. Rakai Project Study Group. N Engl J Med. 2000;342:921-929.
7. Levinson P, Kaul R, Kimani J, et al. Levels of innate immune factors in genital fluids: association of alpha defensins and LL-37 with genital infections and increased HIV acquisition. AIDS. 2009;23:309-317.
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