Immune surveillance below the radar: study offers explanation for acyclovir’s failure to reduce HIV risk

2 October 2009. Related: Basic science and immunology.

Richard Jefferys, TAG

In a recent post on the Merck vaccine trial, I mentioned a new study from Larry Corey’s research group addressing the relationship between HSV-2 infection and enhanced susceptibility to HIV. [1]

The data were presented by Corey at the Keystone conference in March and were published online by Nature Medicine on 2 August 2009. [2]

The background to the work is that HSV-2 infection has been consistently associated with a 2 to 3-fold increased risk of acquiring HIV; a meta-analysis published in 2006 reported a relative risk of 3.1, 2.7 and 1.7 for women, heterosexual men and men who have sex with men, respectively. [3]

Recently analysed data from the Merck vaccine trial are consistent with these findings in that HSV-2-infected participants were found to have approximately double the risk of acquiring HIV infection during the study.

The mechanism by which HSV-2 infection increases HIV acquisition risk is not so clear, however, and has been the subject of debate. The general view is that local inflammation and damage to the integrity of the genital mucosa are plausible ways that HSV-2 infection may increase the chances of HIV transmission. This view led to the logical proposition that suppressing HSV-2 with chronic acyclovir treatment might be a means to also reduce the risk of HIV acquisition. Several large trials have now explored this hypothesis and, while acyclovir treatment was effective at reducing symptomatic HSV-2 reactivations, it did not reduce the incidence of HIV infection.

The new study from Larry Corey’s laboratory set out to try and shed light on these trial results. The same group of researchers has previously shown that immune surveillance of HSV-2 is a far more active process than many had surmised. In a 2007 paper in the Journal of Experimental Medicine, they demonstrated that HSV-2-specific CD8+ T cells gather at sites of subclinical HSV-2 reactivation in the genital skin and persist for at least several months after HSV-2 DNA is no longer detectable. [4]

A year later in the Journal of Infectious Diseases, they published results of an intensive study in which participants took oral and anogenital swabs four times a day for 60 days. Analysing the swabs for HSV-2 DNA, the researchers found that subclinical reactivations were frequent and typically lasted less than 12 hours, showing that there is an ongoing and dynamic effort on the part of the immune system to keep HSV-2 suppressed. [5]

These findings led the researchers to suspect that perhaps elevated levels of activated HSV-2-specific CD4 T cells would be present in the genital mucosa even during chronic acyclovir treatment, and this is exactly what they report in the Nature Medicine paper. The study initially took biopsies of genital skin during an acute, clinically symptomatic lesion and 2, 4 and 8 weeks after healing. Four participants subsequently initiated chronic suppressive acyclovir treatment at the start of their next symptomatic episode and had biopsies taken at 2, 4, 8, 16 & 20 weeks after healing. In all cases, control biopsies were obtained from an unaffected area of genital skin at each timepoint. [2]

During an acute HSV-2 lesion, the researchers found a “massive localised infiltration” of cells. Mean numbers of CD4 and CD8 T cells per mm2 of skin were 655 and 618, respectively, compared to 68 and 55 per mm2 of the unaffected skin sample. Although follow-up biopsies documented gradual clearance of HSV-2 and a decline in inflammation, elevated numbers of CD4 and CD8 T cells remained present locally for months. Eight weeks after healing, a median of 8-fold more CD4 T cells were present at the affected versus the unaffected site. Furthermore, even after 20 weeks of acyclovir treatment, the number of CD4 T cells remained significantly elevated. Additional analyses illustrated that the majority of these CD4 T cells expressed CCR5 and their presence was also associated with a significant increase in the numbers of DC-SIGN-expressing dendritic cells. The enrichment of CCR5-expressing CD4 T cells and DC-SIGN-expressing dendritic cells at the former lesion site was not significantly altered by chronic acyclovir treatment.

The researchers acknowledge in the conclusion to the paper that the number of participants was small, but nevertheless state:: “we feel that our central finding – that HSV reactivation leaves a residual inflammatory response not appreciated clinically – is typical of HSV-2 genital lesions.” They also note that “the wide anatomical distribution of HSV-2 in the male and female genital tract underscores the importance that these localized reservoirs of inflammatory cells are likely to have in HIV acquisition.”

Source: TAG Basic Science web log (03.08.09)

http://tagbasicscienceproject.typepad.com

References

1. http://tagbasicscienceproject.typepad.com/tags_basic_science_vaccin/2009/07/the-role-of-ad5specific-cd4-t-cells-in-enha ncing-risk-of-hiv-acquisition-in-the-merck-vaccine-trial-.html
2. Zhu J et al. Persistence of HIV-1 receptor–positive cells after HSV-2 reactivation is a potential mechanism for increased HIV-1 acquisition. Nature Medicine. Published online:: 2 August 2009 | doi::10.1038/nm.2006.
   http://www.nature.com/nm/journal/vaop/ncurrent/abs/nm.2006.html
3. Freeman EE et al. – Herpes simplex virus 2 infection increases HIV acquisition in men and women: systematic review and meta-analysis of Herpes simplex virus 2 infection increases HIV acquisition in men and women:: systematic review and meta-analysis of longitudinal studies. AIDS:: 2 January 2006 – Volume 20 – Issue 1 – p 73-83. Free full text online.
   http://journals.lww.com/aidsonline/toc/2006/01020
4. Zhu J et al. – Virus-specific CD8+ Tcells accumulate near sensory nerve endings in genital skin during subclinical HSV-2 reactivation. JournalVirus-specific CD8+ T cells accumulate near sensory nerve endings in genital skin during subclinical HSV-2 reactivation. JournalJournal of Experimental Medicine, 2007. Vol204,No3,pages595-603. doi:10.1084/jem.20061792.
   http://jem.rupress.org/cgi/content/full/204/3/595
5. Mark KE et al. Rapidly cleared episodes of herpes simplex virus reactivation in immunocompetent adults. Journal of Infectious Diseases, Rapidly cleared episodes of herpes simplex virus reactivation in immunocompetent adults. Journal of Infectious Diseases, 2008;198:1141–1149. doi: 10.1086/591913.
   http://www.journals.uchicago.edu/doi/full/10.1086/591913