New insights on interactions between HIV-1 and HSV-2

  • Sinéad Delany-Moretlwe
  • Jairam R. Lingappa
  • Connie Celum


Herpes simplex type 2 (HSV-2) infection is common and frequently asymptomatic. Concerns exist about the high prevalence of HSV-2, particularly in areas of high HIV prevalence, because of observations that HSV-2 is associated with an increased risk of HIV acquisition, transmission, and disease progression. Several randomized trials have tested or are testing whether HSV-2 treatment can limit the spread of HIV, with mixed results. Although treatment with acyclovir, 400 mg twice daily, does not reduce HIV incidence, suppressive acyclovir and valacyclovir reduce HIV levels in plasma and in the genital tract. Ongoing trials are evaluating whether HSV suppression will reduce HIV transmission and disease progression. Until a protective HSV-2 or HIV vaccine is available, effective interventions that reduce the effect of HSV-2 on HIV transmission are critically needed.

References and Recommended Reading

  1. 1.
    Looker KJ, Garnett GP, Schmid GP: An estimate of the global prevalence and incidence of herpes simplex virus type 2 infection. Bull World Health Organ 2008, 86:805–812, A.PubMedCrossRefGoogle Scholar
  2. 2.
    Mbopi-Keou FX, Gresenguet G, Mayaud P, et al.: Interactions between herpes simplex virus type 2 and human immunodeficiency virus type 1 infection in African women: opportunities for intervention. J Infect Dis 2000, 182:1090–1096.PubMedCrossRefGoogle Scholar
  3. 3.
    Safrin S, Ashley R, Houlihan C, et al.: Clinical and serologic features of herpes simplex virus infection in patients with AIDS. AIDS 1991, 5:1107–1110.PubMedCrossRefGoogle Scholar
  4. 4.
    Siegal FP, Lopez C, Hammer GS, et al.: Severe acquired immunodeficiency in male homosexuals, manifested by chronic perianal ulcerative herpes simplex lesions. N Engl J Med 1981, 305:1439–1444.PubMedGoogle Scholar
  5. 5.
    Langenberg A, Benedetti J, Jenkins J, et al.: Development of clinically recognizable genital lesions among women previously identified as having “asymptomatic” herpes simplex virus type 2 infection. Ann Intern Med 1989, 110:882–887.PubMedGoogle Scholar
  6. 6.
    Frenkel LM, Garratty EM, Shen JP, et al.: Clinical reactivation of herpes simplex virus type 2 infection in seropositive pregnant women with no history of genital herpes. Ann Intern Med 1993, 118:414–418.PubMedGoogle Scholar
  7. 7.
    Celum C, Wald A, Hughes J, et al.: Effect of aciclovir on HIV-1 acquisition in herpes simplex virus 2 seropositive women and men who have sex with men: a randomised, double-blind, placebo-controlled trial. Lancet 2008, 371:2109–2119.PubMedCrossRefGoogle Scholar
  8. 8.
    Wald A, Zeh J, Selke S, et al.: Reactivation of genital herpes simplex virus type 2 infection in asymptomatic seropositive persons. N Engl J Med 2000, 342:844–850.PubMedCrossRefGoogle Scholar
  9. 9.
    Kamali A, Nunn AJ, Mulder DW, et al.: Seroprevalence and incidence of genital ulcer infections in a rural Ugandan population. Sex Transm Infect 1999, 75:98–102.PubMedCrossRefGoogle Scholar
  10. 10.
    McFarland W, Gwanzura L, Bassett MT, et al.: Prevalence and incidence of herpes simplex virus type 2 infection among male Zimbabwean factory workers. J Infect Dis 1999, 180:1459–1465.PubMedCrossRefGoogle Scholar
  11. 11.
    Corey L, Wald A, Celum CL, Quinn TC: The effects of herpes simplex virus-2 on HIV-1 acquisition and transmission: a review of two overlapping epidemics. J Acquir Immune Defic Syndr 2004, 35:435–445.PubMedCrossRefGoogle Scholar
  12. 12.
    Freeman EE, Weiss HA, Glynn JR, et al.: Herpes simplex virus 2 infection increases HIV acquisition in men and women: systematic review and meta-analysis of longitudinal studies. AIDS 2006, 20:73–83.PubMedCrossRefGoogle Scholar
  13. 13.
    Brown JM, Wald A, Hubbard A, et al.: Incident and prevalent herpes simplex virus type 2 infection increases risk of HIV acquisition among women in Uganda and Zimbabwe. AIDS 2007, 21:1515–1523.PubMedCrossRefGoogle Scholar
  14. 14.
    Koelle DM, Abbo H, Peck A, et al.: Direct recovery of herpes simplex virus (HSV)-specific T lymphocyte clones from recurrent genital HSV-2 lesions. J Infect Dis 1994, 169:956–961.PubMedGoogle Scholar
  15. 15.
    Rebbapragada A, Wachihi C, Pettengell C, et al.: Negative mucosal synergy between Herpes simplex type 2 and HIV in the female genital tract. AIDS 2007, 21:589–598.PubMedCrossRefGoogle Scholar
  16. 16.
    Zhu J, Koelle DM, Cao J, et al.: Virus-specific CD8+ T cells accumulate near sensory nerve endings in genital skin during subclinical HSV-2 reactivation. J Exp Med 2007, 204:595–603.PubMedCrossRefGoogle Scholar
  17. 17.
    Watson-Jones D, Weiss HA, Rusizoka M, et al.: Effect of herpes simplex suppression on incidence of HIV among women in Tanzania. N Engl J Med 2008, 358:1560–1571.PubMedCrossRefGoogle Scholar
  18. 18.
    Mark KE, Wald A, Magaret AS, et al.: Rapidly cleared episodes of herpes simplex virus reactivation in immunocompetent adults. J Infect Dis 2008, 198:1141–1149.PubMedCrossRefGoogle Scholar
  19. 19.
    Posavad CM, Wald A, Kuntz S, et al.: Frequent reactivation of herpes simplex virus among HIV-1-infected patients treated with highly active antiretroviral therapy. J Infect Dis 2004, 190:693–696.PubMedCrossRefGoogle Scholar
  20. 20.
    Strick LB, Wald A, Celum C: Management of herpes simplex virus type 2 infection in HIV type 1-infected persons. Clin Infect Dis 2006, 43:347–356.PubMedCrossRefGoogle Scholar
  21. 21.
    Schacker T, Ryncarz AJ, Goddard J, et al.: Frequent recovery of HIV-1 from genital herpes simplex virus lesions in HIV-1-infected men. JAMA 1998, 280:61–66.PubMedCrossRefGoogle Scholar
  22. 22.
    Mole L, Ripich S, Margolis D, Holodniy M: The impact of active herpes simplex virus infection on human immunodeficiency virus load. J Infect Dis 1997, 176:766–770.PubMedCrossRefGoogle Scholar
  23. 23.
    McClelland RS, Wang CC, Overbaugh J, et al.: Association between cervical shedding of herpes simplex virus and HIV-1. AIDS 2002, 16:2425–2430.PubMedCrossRefGoogle Scholar
  24. 24.
    Diaz JJ, Dodon MD, Schaerer-Uthurralt N, et al.: Post-transcriptional transactivation of human retroviral envelope glycoprotein expression by herpes simplex virus Us11 protein. Nature 1996, 379:273–277.PubMedCrossRefGoogle Scholar
  25. 25.
    Margolis DM, Rabson AB, Straus SE, Ostrove JM: Transactivation of the HIV-1 LTR by HSV-1 immediate-early genes. Virology 1992, 186:788–791.PubMedCrossRefGoogle Scholar
  26. 26.
    Mosca JD, Bednarik DP, Raj NB, et al.: Herpes simplex virus type-1 can reactivate transcription of latent human immunodeficiency virus. Nature 1987, 325:67–70.PubMedCrossRefGoogle Scholar
  27. 27.
    Heng MC, Heng SY, Allen SG: Co-infection and synergy of human immunodeficiency virus-1 and herpes simplex virus-1. Lancet 1994, 343:255–258.PubMedCrossRefGoogle Scholar
  28. 28.
    Kucera LS, Leake E, Iyer N, et al.: Human immunodeficiency virus type 1 (HIV-1) and herpes simplex virus type 2 (HSV-2) can coinfect and simultaneously replicate in the same human CD4+ cell: effect of coinfection on infectious HSV-2 and HIV-1 replication. AIDS Res Hum Retroviruses 1990, 6:641–647.PubMedCrossRefGoogle Scholar
  29. 29.
    Clouse KA, Powell D, Washington I, et al.: Monokine regulation of human immune deficiency virus type 1 expression in a chronically infected human t-cell line. J Immunol 1989, 142:431–438.PubMedGoogle Scholar
  30. 30.
    Paludan SR: Requirements for the induction of interleukin-6 by herpes simplex virus-infected leukocytes. J Virol 2001, 75:8008–8015.PubMedCrossRefGoogle Scholar
  31. 31.
    LeGoff J, Weiss HA, Gresenguet G, et al.: Cervicovaginal HIV-1 and herpes simplex virus type 2 shedding during genital ulcer disease episodes. AIDS 2007, 21:1569–1578.PubMedCrossRefGoogle Scholar
  32. 32.
    Paz-Bailey G, Sternberg M, Puren A, et al.: Impact of episodic acyclovir therapy on genital ulcer duration and HIV shedding from herpetic ulcers among men in South Africa. Presented at the 17th International Society for Sexually Transmitted Diseases Research Conference. Seattle, WA; July 30–August 1, 2007.Google Scholar
  33. 33.
    Zuckerman RA, Lucchetti A, Whittington WL, et al.: Herpes simplex virus (HSV) suppression with valacyclovir reduces rectal and blood plasma HIV-1 levels in HIV-1/HSV-2-seropositive men: a randomized, double-blind, placebo-controlled crossover trial. J Infect Dis 2007, 196:1500–1508.PubMedCrossRefGoogle Scholar
  34. 34.
    Baeten JM, Strick LB, Lucchetti A, et al.: Herpes simplex virus (HSV)-suppressive therapy decreases plasma and genital HIV-1 levels in HSV-2/HIV-1 coinfected women: a randomized, placebo-controlled, cross-over trial. J Infect Dis 2008, 198:1804–1808.PubMedCrossRefGoogle Scholar
  35. 35.
    Nagot N, Ouedraogo A, Foulongne V, et al.: Reduction of HIV-1 RNA levels with therapy to suppress herpes simplex virus. N Engl J Med 2007, 356:790–799.PubMedCrossRefGoogle Scholar
  36. 36.
    Dunne EF, Whitehead S, Sternberg M, et al.: Suppressive acyclovir therapy reduces HIV cervicovaginal shedding in HIV- and HSV-2-infected women, Chiang Rai, Thailand. J Acquir Immune Defic Syndr 2008, 49:77–83.PubMedCrossRefGoogle Scholar
  37. 37.
    Delany S, Clayton T, Mlaba N, et al.: Impact of aciclovir on genital and plasma HIV-1 RNA in HSV-2/HIV-1 coinfected women: a randomised placebo-controlled trial in South Africa. AIDS 2008, in press.Google Scholar
  38. 38.
    Cowan FM, Pascoe SJ, Barlow KL, et al.: A randomised placebo-controlled trial to explore the effect of suppressive therapy with acyclovir on genital shedding of HIV-1 and herpes simplex virus type 2 among Zimbabwean sex workers. Sex Transm Infect 2008, 84:548–553.PubMedCrossRefGoogle Scholar
  39. 39.
    Lingappa JR, Lambdin B, Bukusi EA, et al.: Regional differences in prevalence of HIV-1 discordance in Africa and enrollment of HIV-1 discordant couples into an HIV-1 prevention trial. PLoS ONE 2008, 3:e1411.CrossRefGoogle Scholar
  40. 40.
    Ameli N, Bacchetti P, Morrow RA, et al.: Herpes simplex virus infection in women in the WIHS: epidemiology and effect of antiretroviral therapy on clinical manifestations. AIDS 2006, 20:1051–1058.PubMedCrossRefGoogle Scholar
  41. 41.
    Ouedraogo A, Nagot N, Vergne L, et al.: Impact of suppressive herpes therapy on genital HIV-1 RNA among women taking antiretroviral therapy: a randomized controlled trial. AIDS 2006, 20:2305–2313.PubMedCrossRefGoogle Scholar
  42. 42.
    Lisco A, Vanpouille C, Tchesnokov EP, et al.: Acyclovir is activated into a HIV-1 reverse transcriptase inhibitor in herpesvirus-infected human tissues. Cell Host Microbe 2008, 4:260–270.PubMedCrossRefGoogle Scholar
  43. 43.
    McMahon MA, Siliciano JD, Lai J, et al.: The antiherpetic drug acyclovir inhibits HIV replication and selects the V75I reverse transcriptase multidrug resistance mutation. J Biol Chem 2008, 283:31289–31293.PubMedCrossRefGoogle Scholar
  44. 44.
    Cowan FM, Humphrey JH, Ntozini R, et al.: Maternal herpes simplex virus type 2 infection, syphilis and risk of intra-partum transmission of HIV-1: results of a case control study. AIDS 2008, 22:193–201.PubMedCrossRefGoogle Scholar
  45. 45.
    Bollen LJ, Whitehead SJ, Mock PA, et al.: Maternal herpes simplex virus type 2 coinfection increases the risk of perinatal HIV transmission: possibility to further decrease transmission? AIDS 2008, 22:1169–1176.PubMedCrossRefGoogle Scholar
  46. 46.
    Drake AL, John-Stewart GC, Wald A, et al.: Herpes simplex virus type 2 and risk of intrapartum human immunodeficiency virus transmission. Obstet Gynecol 2007, 109(2 Pt 1):403–409.Google Scholar
  47. 47.
    Mellors JW, Munoz A, Giorgi JV, et al.: Plasma viral load and CD4+ lymphocytes as prognostic markers of HIV-1 infection. Ann Intern Med 1997, 126:946–954.PubMedGoogle Scholar
  48. 48.
    Ioannidis JP, Collier AC, Cooper DA, et al.: Clinical efficacy of high-dose acyclovir in patients with human immunodeficiency virus infection: a meta-analysis of randomized individual patient data. J Infect Dis 1998, 178:349–359.PubMedGoogle Scholar
  49. 49.
    Smith MS, Thresher RJ, Pagano JS: Inhibition of human immunodeficiency virus type 1 morphogenesis in T cells by alpha interferon. Antimicrob Agents Chemother 1991, 35:62–67.PubMedGoogle Scholar
  50. 50.
    Modjarrad K, Chamot E, Vermund SH: Impact of small reductions in plasma HIV RNA levels on the risk of heterosexual transmission and disease progression. AIDS 2008, 22:2179–2185.PubMedCrossRefGoogle Scholar
  51. 51.
    Nagot N, Ouedraogo A, Konate I, et al.: Roles of clinical and subclinical reactivated herpes simplex virus type 2 infection and human immunodeficiency virus type 1 (HIV-1)-induced immunosuppression on genital and plasma HIV-1 levels. J Infect Dis 2008, 198:241–249.PubMedCrossRefGoogle Scholar
  52. 52.
    Reyes M, Shaik NS, Graber JM, et al.: Acyclovir-resistant genital herpes among persons attending sexually transmitted disease and human immunodeficiency virus clinics. Arch Intern Med 2003, 163:76–80.PubMedCrossRefGoogle Scholar
  53. 53.
    Gupta R, Hill EL, McClernon D, et al.: Acyclovir sensitivity of sequential herpes simplex virus type 2 isolates from the genital mucosa of immunocompetent women. J Infect Dis 2005, 192:1102–1107.PubMedCrossRefGoogle Scholar
  54. 54.
    Swetter SM, Hill EL, Kern ER, et al.: Chronic vulvar ulceration in an immunocompetent woman due to acyclovir-resistant, thymidine kinase-deficient herpes simplex virus. J Infect Dis 1998, 177:543–550.PubMedGoogle Scholar
  55. 55.
    Keller MJ, Zerhouni-Layachi B, Cheshenko N, et al.: PRO 2000 gel inhibits HIV and herpes simplex virus infection following vaginal application: a double-blind placebo-controlled trial. J Infect Dis 2006, 193:27–35.PubMedCrossRefGoogle Scholar
  56. 56.
    Bailey RC, Moses S, Parker CB, et al.: Male circumcision for HIV prevention in young men in Kisumu, Kenya: a randomised controlled trial. Lancet 2007, 369:643–656.PubMedCrossRefGoogle Scholar
  57. 57.
    Gray RH, Kigozi G, Serwadda D, et al.: Male circumcision for HIV prevention in men in Rakai, Uganda: a randomised trial. Lancet 2007, 369:657–666.PubMedCrossRefGoogle Scholar
  58. 58.
    Tobian A, Serwadda D, Quinn T, et al.: Trial of male circumcision: prevention of HSV-2 in men and vaginal infections in female partners, Rakai, Uganda. Presented at the 15th Conference on Retroviruses and Opportunistic Infections. Boston, MA; February 3–6, 2008.Google Scholar

Copyright information

© Current Medicine Group, LLC 2009

Authors and Affiliations

  • Sinéad Delany-Moretlwe
    • 1
  • Jairam R. Lingappa
  • Connie Celum
  1. 1.Reproductive Health and HIV Research UnitUniversity of WitwatersrandHillbrow, JohannesburgSouth Africa

Personalised recommendations