There is now extensive evidence that herpesviruses can interact with human immunodeficiency virus (HIV) in vitro. To determine if such interactions could be operative in vivo, evidence from AIDS autopsy series are reviewed. Using basic histopathological techniques, cytomegalovirus (CMV) and HIV coinfection of various individual ceils has been demonstrated. Using cell culture, CMV has been detected in 66% and herpes simplex virus in 11% of patients. Using immunocytochemistry, human herpesvirus type 6 (HHV-6) has been found in virtually all tissue sections. The hypothesis that these viruses contribute to the death of individuals with AIDS is supported by the results of two double-blind, placebo-controlled randomized trials of high-dose aciclovir and an observational study of the same drug. All three studies have shown improved survival. Thus, the case is made that herpesviruses act as co-factors of HIV disease, and that inhibition of such infections represents a potential way of reducing mortality in those with AIDS.
This paper was presented as the case for in a debate on ‘Herpesviruses as co-factors of HIV disease’. The case against was made by Don Jeffries (see page 22)
AnderssonJ.BrittonS.ErnbergI.AnderssonU.HenleW.SkoldenbergB., and TissellA. (1986) Effect of aciclovir on infectious mononucleosis: a double-blind, placebo-controlled study. J Infect Dis153: 283–290.
2.
BalfourH.H.JrChaceB.A.StapletonJ.T.SimmonsR.L., and FrydD.S. (1989) A randomized, placebo-controlled trial of oral aciclovir for the prevention of cytomegalovirus disease in recipients of renal allografts. N Engl J Med320: 1381–1387.
3.
BelecL.GrayF.MikolJ.ScaravilliF.MhiriC.SobelA., and PorierJ. (1990) Cytomegalovirus (CMV) encephalomyeloradiculitis and human immunodeficiency virus (HIV) encephalitis: presence of HIV and CMV co-infected multinucleated giant cells. Acta Neuropathologica81: 99–104.
4.
BurnsW.H., and SandfordG.R. (1990) Susceptibility of human herpesvirus 6 to antivirals in vitro. J Infect Dis162: 634–637.
5.
ClouseK.A.RobbinsP.B.FernieB.OstroveJ.M., and FauciA.S. (1989) Viral antigen stimulation of the production of human monokines capable of regulating HIV1 expression. J Immunol143: 470–475.
6.
CooperD.A.PehrsonP.O.PedersenC.MoroniM.OksenhendlerE.RozenbaumW.ClumeckN.FaberV.StilleW.HirschelB. (1993) The efficacy and safety of zidovudine alone or as cotherapy with aciclovir for the treatment of patients with AIDS and AIDS-related complex: a double-blind randomized trial. European-Australian Collaborative Group. AIDS7: 197–207.
7.
CorbellinoM.LussoP.GalloR.C.ParraviciniC.GalliM., and MoroniM. (1993) Disseminated human herpesvirus 6 infection in AIDS (Letter). Lancet342:1242.
8.
DavisM.G.KenneyS.C.KamineJ.PaganoJ.S., and HuangE.S. (1987) Immediate-early gene region of human cytomegalovirus trans-activates the promoter of human immunodeficiency virus. Proc Natl Acad Sci USA84: 8642–8646.
9.
FinkleC.TapperM.A.KnoxK.K., and CarriganD.R. (1991) Co-infection of cells with the human immunodeficiency virus and cytomegalovirus in lung tissues of patients with AIDS. J AIDS4: 735–737.
10.
GendelmanH.E.PhelpsW.FeigenbaumL.OstroveJ.M.AdachiA.HowleyP.M.KhouryG.GinsbergH.S., and MartinM.A. (1986) Trans-activation of the human immunodeficiency virus long terminal repeat sequence by DNA viruses. Proc Natl Acad Sci USA83: 9759–9763.
11.
GriffithsP.D. (1992) Studies to define viral co-factors for human immunodeficiency virus. Infect Agents Dis1: 237–244.
12.
JeffriesD. (1995) Herpesviruses as co-factors of HIV disease: case not proven. Antiviral Chem Chemother6 (Suppl. 1): 22–27.
13.
KenneyS.KamineJ.MarkovitzD.FenrickR., and PaganoJ. (1988) An Epstein-Barr virus immediate-early gene product trans-activates gene expression from the human immunodeficiency virus long terminal repeat. Proc Natl Acad Sci USA85: 1652–1656.
14.
KnoxK.K., and CarriganD.R. (1994) Disseminated active HHV-6 infections in patients with AIDS. Lancet343: 577–578.
15.
KovalV.ClarkC.VaishnavM.SpectorS.A., and SpectorD.H. (1991) Human cytomegalovirus inhibits human immunodeficiency virus replication in cells productively infected by both viruses. J Virol65: 6969–6978.
16.
LussoP.De MariaA.MalnatiM.LoriF.DeRoccoS.E.BaselerM., and GalloR.C. (1991) Induction of CD4 and susceptibility to HIV-1 infection in human CD8+ T lymphocytes by human herpesvirus 6. Nature349: 533–535.
17.
LussoP.EnsoliB.MarkhamP.D.AblashiD.V.SalahuddinS.Z.TschachlerE.Wong-StaalF., and GalloR.C. (1989) Productive dual infection of human CD4+ T lymphocytes by HIV-1 and HHV-6. Nature337: 370–373.
18.
LussoP.LoriF., and GalloR.C. (1990) CD4-independent infection by human immunodeficiency virus type 1 after phenotypic mixing with human T-cell leukemia viruses. J Virol64: 6341–6344.
19.
McKeatingJ.A.GriffithsP.D., and WeissR.A. (1990) HIV susceptibility conferred to human fibroblasts by cytomegalovirus-induced Fc receptor. Nature343:659–661.
20.
NelsonJ.A.Reynolds-KohlerC.OldstoneM.B., and WileyC.A. (1988) HIV and HCMV co-infect brain cells In patients with AIDS. Virology165: 286–290.
21.
PetersonP.K.GekkerG.ChaoC.C.HuS.X.EdelmanC.BalfourH.H.Jr, and VerhoefJ. (1992) Human cytomegalovirus-stimulated peripheral blood mononuclear cells induce HIV-1 replication via a tumor necrosis factor-alpha-mediated mechanism. J Clin Invest89: 574–580.
22.
PillayD.LipmanM.C.LeeC.A.JohnsonM.A.GriffithsP.D., and McLaughlinJ.E. (1993) A clinico-pathological audit of opportunistic viral infections in HIV-infected patients. AIDS7: 969–974.
23.
RiceA.P., and MathewsM.B. (1988) Trans-activation of the human immunodeficiency virus long terminal repeat sequences, expressed in an adenovirus vector, by the adenovirus E1A 13S protein. Proc Natl Acad Sci USA85: 4200–4204.
24.
SiddiquiA.GaynorR.SrinivasanA.MapolesJ., and FarrR.W. (1989) Trans-activation of viral enhancers including long terminal repeat of the human immunodeficiency virus by the hepatitis B virus X protein. Virology169: 479–484.
25.
SiekevitzM.JosephsS.F.DukovichM.PefferN.Wong-StaalF., and GreeneW.C. (1987) Activation of the HIV-1 LTR by T cell mitogens and the trans-activator protein of HTLV-I. Science238:1575–1578.
26.
SkolnikP.R.PomerantzR.J.de la MonteS.M.LeeS.F.HsiungG.D.FoosR.Y.CowanG.M.KosloffB.R.HirschM.S., and PeposeJ.M. (1989) Dual infection of retina with human immunodeficiency virus type 1 and cytomegalovirus. Am J Ophthalmol107: 361–372.
27.
SteinD.S.GrahamN.M.ParkL.P.HooverD.R.PhairJ.P.DetelsR.HoM., and SaahA.J. (1994) The effect of the interaction of aciclovir with zidovudine on progression to AIDS and survival. Analysis of data in the Multicenter AIDS Cohort Study. Ann Intern Med121:100–108.
28.
WeissR.A.ClaphamP.R.Cheingsong-PopovR.DalgleishA.G.CarneC.A.WellerI.V., and TedderR.S. (1985) Neutralization of human T-lymphotropic virus type III by sera of AIDS and AIDS-risk patients. Nature316: 69–72.
29.
WileyC.A., and NelsonJ.A. (1988) Role of human immunodeficiency virus and cytomegalovirus in AIDS encephalitis. Am J Pathol133: 73–81.
30.
YouleM.S.GazzardB.G.JohnsonM.A.CooperD.A.HoyJ.F.BuschH.RufB.GriffithsP.D.StephensonS.L.DancoxM. (1994) Effects of high-dose oral aciclovir on herpesvirus disease and survival in patients with advanced HIV disease: a double-blind, placebo-controlled study, European-Australian aciclovir Study Group. AIDS8: 641–649.
31.
ZhuZ.H.ChenS.S., and HuangA.S. (1990) Phenotypic mixing between human immunodeficiency virus and vesicular stomatitis virus or herpes simplex virus. J AIDS3: 215–219.
