Important note: Information in this article was accurate in December 1998. The state of the art may have changed since the publication date.Infections with herpes simplex viruses (HSV) are very common among persons with HIV infection. Despite the frequent co-infection with both viruses, the interactions between HSV and HIV have been not fully elucidated. However, evidence suggests that these interactions occur on epidemiologic, clinical, and cellular levels:
The clinical significance of these interactions has not been well defined. In this article, we review the current information about HSV-HIV interactions and suggest future directions for this research.
Genital herpes and transmission and acquisition of HIV
Several studies have found that persons with HIV infection also have high prevalence of HSV-2 infection. However, it remains unclear whether HSV-2 is a marker for high risk sex behavior, or whether it truly facilitates acquisition of HIV infection. Both epidemiologic studies of HIV acquisition and the biology of HSV lesion suggest that the latter is true.
At least five studies conducted in various populations suggest that those with HSV-2 infection are more likely to be HIV infected. The increase in risk of HIV infection ranges from 2-fold to 7.5-fold. For example, in a longitudinal study of heterosexual couples in Europe, those susceptible partners who had a history of genital ulcers were 5.2 times as likely to acquire HIV than the susceptible partners who did not have a history of genital ulcers.
Two biological aspects of genital herpes support the hypothesis that HSV-2 facilitates HIV acquisition. Genital ulcers cause a mucosal disruption, which may allow entry of HIV. Also, genital herpes lesions attract activated CD4 cells that act as target cells for HIV attachment.
Fewer data are available on the relationship between HSV-2 infection and HIV transmission, as transmitters of disease are more difficult to study. However, in an early description of a cluster of HIV infection among women, a man who had HIV infection unknowingly infected 14 of 19 women with whom he had sexual relations. He had a history of recurrent genital herpes.
Other studies have also suggested that transmission of HIV is more likely to occur from a person who has genital ulcers. This has been shown both for female to male as well male to female transmission. In 1989, Kreiss and colleagues detected HIV in 4 of 36 ulcers in women; subsequently, HIV has also been detected in ulcers among men. These early studies were done in Kenya where chancroid was the predominant cause of ulcerations. As genital herpes is the most common cause of genital ulcers in the United States, we have investigated whether we can recover HIV from genital herpes lesions in persons with HIV infection.
Twelve men with a history of genital herpes were enrolled in this study. The median CD4 count was 186 and the median plasma HIV RNA 41,000 (this study was conducted prior to introduction of protease inhibitors). None of the participants had a history of difficult to treat genital herpes. The 12 clients were followed for 26 episodes of genital herpes; 23 healed without anti-herpes therapy, while 3 healed after administration of acyclovir. Clients were seen within 24 hours of new recurrence and then every other day, and swab samples were obtained from their genital lesions for HIV polymerase chain reaction (PCR) assay. HIV RNA was detected in 25 out of 26 recurrences and in 116 of 170 lesion samples. Three-fourths (75%) of the HIV RNA-positive samples contained 10,000 or more copies of HIV/ml. In addition, the PCR signal was detected only when reverse transcriptase was added to the reaction, suggesting that only virion RNA was present and not proviral DNA. HIV was detected in lesions of people with high and low viral loads, and regardless of concurrent antiretroviral therapy. In one person in whom acyclovir was started on the fifth day of his genital herpes recurrence, the levels of HIV RNA in lesions fell rapidly as the lesions healed.
This study supports the hypothesis that persons who have HIV and genital herpes may transmit HIV infection to others more easily than those who are not HSV-2 infected. In addition, it suggests that therapy of genital herpes may curb transmission of HIV to susceptible sexual partners.
High rates of HSV shedding in the genital tract of the HIV infected persons Large, chronic, persistent herpes ulcers were among the first opportunistic infections described in homosexual men in 1981. Since that time, advanced HIV infection has been associated with severe genital herpes and the emergence of acyclovir resistance. Because of the unusual severity of genital herpes in some HIV infected persons, persistent herpetic ulcerations are an AIDS-defining diagnosis. Yet in spite of the anecdotal reports of painful and difficult to treat genital herpes in some persons with HIV infection, the natural history of HSV in HIV infected persons has not been well defined. Clinical experience suggests the rate of clinical recurrences (outbreaks) may be increased and that the response to antiviral therapy may be delayed.
To assess the impact of HIV infection on the natural history of genital herpes, we followed prospectively a cohort of 68 men with HIV and HSV-2 infection. The men obtained daily swabs for viral culture from the urethra, penile skin, and the perianal area, and maintained a diary of recurrences. The median duration of study participation was 55 days. We found that, overall, the rate of shedding was very high: HSV-2 was isolated on 9.7% of days of cultures. In comparison, HIV seronegative men have a significantly lower rate of shedding: 3.3% of days for men who have sex with men (MSM), and 4.7% for heterosexual men in two separate studies.
Shedding was especially high in the perianal area, where virus was isolated on 8.6% of the days. Of interest, the most common site of shedding among MSM men who are HIV-negative is also the perianal area (2.9% of days), while among heterosexual men the most common site is the penile skin (3.3% of days). Most of the increase in the total shedding rate is accounted for by a dramatic increase in the subclinical shedding rate, defined as the presence of the virus on skin in the absence of herpes lesions. The subclinical shedding rate was 7.3% of days among HIV-positive MSM, compared with 2.4% of HIV-negative MSM and 2.2% of HIV-negative heterosexual men.
Thus it appears that the viral shedding rate is about three-fold higher in HIV-positive versus HIV-negative men. The shedding rate was especially increased among men who have CD4 counts below 200: the risk of shedding was twice as high among men with CD4 counts less than 200 versus those with higher CD4 counts. Therefore, the increase in the rate of viral shedding appeared closely related to the degree of immunosuppression.
In a smaller group of people, we also examined viral shedding using the HSV DNA polymerase chain reaction (PCR) test. This test was developed at the University of Washington and detects minute amounts HSV DNA (1 to 10 copies/sample). Among 14 men who were studied with both viral culture and HSV DNA PCR test, HSV was isolated in culture on 25% of days, but HSV DNA was detected on 48% of the days. In fact, 5 of 14 men had HSV DNA detected on more than 50% of the days. The high rate of positivity by both culture and PCR was especially striking in men with CD4 counts under 200.
The HSV DNA PCR assay is also able to estimate the number of viral copies present in each sample. Using this semiquantitative measure, we found that people with a CD4 count under 200 had 10 times the HSV DNA in the swab samples than people with higher CD4 counts had.
Therefore, it is clear that persons with HIV-induced immunosuppression not only shed HSV more frequently, but also that the shedding is associated with much more virus on the genital skin. HSV reactivation upregulates HIV replication.
Several in-vitro laboratory studies have indicated that certain regulatory HSV proteins (ICPO, ICP27, and VP16) can upregulate HIV replication. In addition, both HSV-2 and HIV can co-infect CD4+ cells suggesting that these viruses may interact frequently in vivo. At the same time, several clinical studies have shown that opportunistic infections, or other means of immune activation (such as Pneumocystis carinii pneumonia, bacterial pneumonia, tuberculosis, or immunizations) can stimulate HIV replication and, at least transiently, increase viral load. Recently, Mole and colleagues have shown that the plasma HIV viral load increases in people with recurrences of genital herpes. It is not known how these increases contribute to overall progression of HIV disease.
Intriguing results have also been obtained from clinical trials that suggested that administration of acyclovir is associated with increased survival in HIV infected persons. While not all of the studies found that effect, there is speculation that reactivation of HSV may accelerate progression of HIV disease.
To examine this issue, we followed 12 people (whose median CD4 count was 246) who were on stable antiretroviral therapy (prior to introduction of protease inhibitors). Clients with serial plasma HIV viral loads were evaluated, initially without acyclovir, and then while being treated with acyclovir 800 mg tid (three times a day).
The median period of observation was 65 prior days prior to acyclovir and 62 days on acyclovir therapy. Plasma HIV RNA was determined on average twice a week during these observations. We found that the HIV RNA decreased from a mean of 25,527 to 16,444 copies/ml, a 35% decrease. Also of interest, the decrease was observed in all 12 people. This study supports the observation that acyclovir may slow the progression of HIV disease by preventing reactivation of HSV.
Currently available data suggest that several important interactions occur between HSV and HIV. First, HIV shedding from genital herpes lesions is frequent. Therefore, HSV is likely to facilitate transmission of HIV to uninfected sexual partners. Second, HSV shedding in men with HIV infection is chronic and mostly subclinical. Because men are not aware when they are shedding HSV, they may engage in unsafe sex during HSV reactivation, increasing the risk of transmission of both HSV and HIV. Third, acyclovir therapy appears to decrease plasma HIV RNA. This supports the importance of HSV as an endemic opportunistic infection and suggests that chronic antiherpes therapy may provide benefit in some persons with HIV infection.
These studies leave several questions unanswered:
Any person interested in participation in studies designed to answer these important questions is invited to call the University of Washington Virology Research Clinic at 206-720-4340 for more information.
Anna Wald, M.D., Department of Medicine, University of Washington, Seattle, Washington;
Timothy Schacker, M.D., Department of Medicine, University of Washington, Seattle, Washington, currently at University of Minnesota, Minneapolis, Minnesota;
Lawrence Corey, M.D., Departments of Laboratory and Medicine, University of Washington, Program Infectious Diseases, Fred Hutchinson Cancer Research Center, Seattle, Washington
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