Download Article PDF/SlidesHerpesviruses have large genomes and contain approximately 35 virion genes—all of which encode a number of enzymes involved in nucleic acid metabolism, DNA syntheses, and protein processing—making them a complex group of viruses. The Herpesviruses are widely separated in terms of genomic sequence and proteins, but all are similar in terms of virion structure and genomic organization.
Of the 100 or so herpesviruses known to infect animals, eight are known to establish infection and cause disease in humans. These human herpesviruses can be divided into three sub-families: Alphaherpesvirinae, Betaherpesvirinae, and Gammaherpesvirinae.
In the Alphaherpesvirinae subfamily are the following: simplexvirus (herpes simplex virus 1 [HSV-1] and 2 [HSV-2]) and varicellovirus (varicella-zoster virus [VZV]). “Alpha herpes viruses are the most aggressive,” Dr. Balfour said. “They will infect a large variety of cell types and tissues and can reproduce very quickly. In turn, they have been the favorite targets of antiviral chemotherapy.”
In the Betaherpesvirinae subfamily: cytomegalovirus (CMV) and roseolovirus (human herpes virus 6 and 7 [HHV-6 and HHV-7]). “These viruses are much more selective in the tissues and cells they infect,” added Dr. Balfour. “They are harder to grow in the laboratory and are much more difficult to treat.”
In the Gammaherpesvirinae subfamily there is lymphocryptovirus (Epstein-Barr virus [EBV]) and human herpesvirus 8 (HHV-8, also known as Kaposi’s sarcoma-associated herpes virus [KSHV]).
To review each of these viruses, even as they relate to HIV infection, would be an enormous undertaking. In turn, PRN recently asked Dr. Henry Balfour, Jr., to crystallize some of the most recent data related to HSV, VZV, CMV, and EBV, in the context of HIV infection, and the direction of research we can expect to see in the near future.
“Recent clinical and basic science research findings do impact the management of these infections in HIV-infected persons,” Dr. Balfour said. “With HSV-2, we’ve learned more about its effect on transmission of HIV. With VZV, new data are available regarding the use of the chickenpox vaccine in people with HIV. CMV research is also telling us more about the use of CMV viral load as a marker of disease progression in HIV-infected patients, even those responding well to antiretroviral therapy. There is also the issue of quantitative EBV virology, which could have a number of implications for HIV-positive patients at risk for complications associated with this infection.”
It is well known that sexual transmission of HIV is facilitated by the presence of genital ulcer disease, including the common HSV-2 infection. In discussing the impact of prevalent and incident HSV-2 infection upon the acquisition of HIV, Dr. Balfour focused on data published last year in the Journal of Infectious Diseases, involving the search for HSV-2 antibodies in stored serum samples from a cohort of 2,732 HIV-negative patients attending four clinics in Pune, India (Reynolds, 2003).
Incident HSV-2 infection was defined as serologically “recent” if a negative HSV-2-specific antibody result could be documented within the previous six months. Incident HSV-2 infection was defined as serologically “remote” if greater than six months had elapsed since the last negative test result. Prevalent HSV-2 infection was defined as the percentage of patients positive for HSV-2 at entry.
Of the 2,732 individuals enrolled, 2,260 were male, 463 were female, and 9 were eunuchs. The prevalence of HSV-2 at enrollment was 43%. The HSV-2 incidence was 11.4 per 100 person-years, and the HIV incidence was 5.9 cases per 100 person-years.
The HIV incidence was 3.6 per 100 person-years among persons without evidence of HSV-2 infection, 7.5 per 100 person-years among persons with prevalent or remote incident HSV-2 infection, and 22.6 per 100 person-years among persons with recent incident HSV-2 infection.
The interaction between clinically apparent or self-reported genital ulcer disease and HSV-2 serostatus was also investigated. Of the 217 individuals with serologic evidence of incident HSV-2 infection, 51 (23%) had a genital lesion documented at the same visit at which seroconversion was demonstrated. Using a proportional hazards model, the investigators found that the presence of asymptomatic prevalent HSV-2 infection conferred an adjusted hazard ratio for HIV infection of 2.14 (compared with no genital ulceration and negative results of serologic testing for HSV-2). Symptomatic prevalent HSV-2 infection conferred an adjusted hazard ratio of 5.06.
In short, this study demonstrated that individuals experiencing incident HSV-2 infections are at the greatest risk of HIV acquisition, compared with individuals not infected with HSV-2 or who have prevalent HSV-2 infection. The individuals with serologic evidence of recent incident HSV-2 infection had the highest HIV incidence, illustrating that recent infection with HSV-2 is independently associated with HIV acquisition.
Dr. Balfour pointed out that some recent in vitro studies have helped to explain the association between HSV-2 and HIV. First, some studies have demonstrated that HSV-2 infection may increase the risk of HIV acquisition through the influx of susceptible, host CD4+ cells to the infected area. Studies have also demonstrated that HSV-2 has the ability to enhance HIV replication. In the Pune study, the investigators suggested that the elevated risk of HIV acquisition among individuals with exposure to recent incident HSV-2 may reflect a more vigorous immune response in individuals who are immunologically naive to HSV-2. In turn, further studies examining the local immune response to incident HSV-2 infection may help explain the elevated risk of HIV acquisition that is associated with exposure to incident HSV-2.
“We definitely need to see more data from studies like this,” Dr. Balfour commented. “But there are some take-home implications for clinicians to think about. We clearly need to be more aggressive in terms of treating HSV-2 infection. Even in some patients with asymptomatic infection, there is viral shedding that seems to confer some risk of acquiring HIV infection.” As for preventing HSV-2 with the use of a vaccine, Dr. Balfour explained that the issue is wide open. “The development of herpes vaccines, particularly genital herpes vaccines, has been checkered with a lot of pitfalls and some qualified successes. But we’re still hoping for a breakthrough.”
| HSV-2 and HIV Transmission | Top of page |
Incident HSV-2 infection was defined as serologically “recent” if a negative HSV-2-specific antibody result could be documented within the previous six months. Incident HSV-2 infection was defined as serologically “remote” if greater than six months had elapsed since the last negative test result. Prevalent HSV-2 infection was defined as the percentage of patients positive for HSV-2 at entry.
Of the 2,732 individuals enrolled, 2,260 were male, 463 were female, and 9 were eunuchs. The prevalence of HSV-2 at enrollment was 43%. The HSV-2 incidence was 11.4 per 100 person-years, and the HIV incidence was 5.9 cases per 100 person-years.
The HIV incidence was 3.6 per 100 person-years among persons without evidence of HSV-2 infection, 7.5 per 100 person-years among persons with prevalent or remote incident HSV-2 infection, and 22.6 per 100 person-years among persons with recent incident HSV-2 infection.
The interaction between clinically apparent or self-reported genital ulcer disease and HSV-2 serostatus was also investigated. Of the 217 individuals with serologic evidence of incident HSV-2 infection, 51 (23%) had a genital lesion documented at the same visit at which seroconversion was demonstrated. Using a proportional hazards model, the investigators found that the presence of asymptomatic prevalent HSV-2 infection conferred an adjusted hazard ratio for HIV infection of 2.14 (compared with no genital ulceration and negative results of serologic testing for HSV-2). Symptomatic prevalent HSV-2 infection conferred an adjusted hazard ratio of 5.06.
In short, this study demonstrated that individuals experiencing incident HSV-2 infections are at the greatest risk of HIV acquisition, compared with individuals not infected with HSV-2 or who have prevalent HSV-2 infection. The individuals with serologic evidence of recent incident HSV-2 infection had the highest HIV incidence, illustrating that recent infection with HSV-2 is independently associated with HIV acquisition.
Dr. Balfour pointed out that some recent in vitro studies have helped to explain the association between HSV-2 and HIV. First, some studies have demonstrated that HSV-2 infection may increase the risk of HIV acquisition through the influx of susceptible, host CD4+ cells to the infected area. Studies have also demonstrated that HSV-2 has the ability to enhance HIV replication. In the Pune study, the investigators suggested that the elevated risk of HIV acquisition among individuals with exposure to recent incident HSV-2 may reflect a more vigorous immune response in individuals who are immunologically naive to HSV-2. In turn, further studies examining the local immune response to incident HSV-2 infection may help explain the elevated risk of HIV acquisition that is associated with exposure to incident HSV-2.
“We definitely need to see more data from studies like this,” Dr. Balfour commented. “But there are some take-home implications for clinicians to think about. We clearly need to be more aggressive in terms of treating HSV-2 infection. Even in some patients with asymptomatic infection, there is viral shedding that seems to confer some risk of acquiring HIV infection.” As for preventing HSV-2 with the use of a vaccine, Dr. Balfour explained that the issue is wide open. “The development of herpes vaccines, particularly genital herpes vaccines, has been checkered with a lot of pitfalls and some qualified successes. But we’re still hoping for a breakthrough.”
| Conclusion | Top of page |
| References | Top of page |
