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Journal of Clinical Virology 35 (2006) 489–492 CMV as a cofactor enhancing progression of AIDS Paul D Griffiths Centre for Virology, The Royal Free and University College Medical School, Hampstead Campus, Rowland Hill Street, London NW3 2PF, UK Received 12 June 2005; accepted 18 October 2005 Abstract Background: Cytomegalovirus (CMV) has been proposed as a cofactor driving HIV pathogenicity since the late 1980s. Potential mechanisms which CMV could use as a cofactor have been described in vitro and potential criteria for assessing cofactor activity in vivo have been proposed. Objective: To determine if recent publications have added new information to these in vitro or in vivo studies since the author last reviewed this subject in 1998. Study design: Literature survey prior to presenting an overview lecture. Results: No new in vitro mechanisms have been described though several clinical cohort studies are consistent with the possibility that active CMV infection can act as a cofactor. One study published in 1999 showed that mortality in AIDS patients was driven more by CMV viral load than HIV viral load. Although highly active antiretroviral therapy (HAART) has now greatly controlled end organ disease caused by CMV, a recent study showed that CMV viraemia was still strongly associated with death in AIDS patients. Conclusions: (1) CMV remains important in the era of HAART. (2) CMV has been underestimated as an important cofactor since the beginning of the AIDS epidemic. © 2005 Elsevier B.V. All rights reserved. Keywords: CMV; HIV; Cofactor; Pathogenesis; AIDS 1. Introduction Since the first cases of AIDS were defined in 1981, CMV end organ disease has been an AIDS defining opportunistic infection. In this review, I will give a historical perspective to suggest that throughout all of this time, including the current era of highly active antiretroviral therapy (HAART), CMV has also acted as a cofactor, driving the pathogenicity of HIV. I will particularly focus on new information which has become available since I last reviewed this subject in 1998 (Griffiths, 1998). 1.1. In vitro mechanisms There are a variety of mechanisms which herpesviruses such as CMV could use to function as a cofactor, defined as Tel.: +44 20 7830 2997; fax: +44 20 7830 2854. E-mail address: [email protected]. “an infectious agent which interacts at the molecular or cel- lular level to promote HIV pathogenicity” (Griffiths, 1992). These mechanisms are categorised in Table 1 according to whether HIV and CMV infect the same or neighbouring cells. The mechanisms are further illustrated in Fig. 1a and b according to whether the net result is to activate HIV gene expression or to alter the tropism of HIV. As illustrated in Fig. 1a, CMV could activate latent provi- ral HIV DNA by introducing its transactivator proteins into the same cell (Davis et al., 1987). Alternatively, CMV could reside in a bystander cell and release cytokines which acti- vate HIV latent provirus through signal transduction (Clouse et al., 1989). In the special case where HIV is latent in a T memory cell whose cognate antigen receptor is specific for a CMV-encoded protein, CMV could release that antigen from a bystander cell so activating latent HIV provirus (Peterson et al., 1992)(Fig. 1a). Alternatively, as shown in Fig. 1b CMV could alter the tropism of HIV. If CMV infected the same cell which is producing HIV particles, then HIV could poten- tially form pseudotypes which would no longer be restricted 1386-6532/$ – see front matter © 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.jcv.2005.10.016

CMV as a cofactor enhancing progression of AIDS

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Page 1: CMV as a cofactor enhancing progression of AIDS

Journal of Clinical Virology 35 (2006) 489–492

CMV as a cofactor enhancing progression of AIDS

Paul D Griffiths∗

Centre for Virology, The Royal Free and University College Medical School, Hampstead Campus, Rowland Hill Street, London NW3 2PF, UK

Received 12 June 2005; accepted 18 October 2005

Abstract

Background: Cytomegalovirus (CMV) has been proposed as a cofactor driving HIV pathogenicity since the late 1980s. Potential mechanismswhich CMV could use as a cofactor have been described in vitro and potential criteria for assessing cofactor activity in vivo have beenproposed.Objective: To determine if recent publications have added new information to these in vitro or in vivo studies since the author last reviewedthis subject in 1998.Study design: Literature survey prior to presenting an overview lecture.Results: No new in vitro mechanisms have been described though several clinical cohort studies are consistent with the possibility that activeC viral loadt y CMV, arC ince theb©

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MV infection can act as a cofactor. One study published in 1999 showed that mortality in AIDS patients was driven more by CMVhan HIV viral load. Although highly active antiretroviral therapy (HAART) has now greatly controlled end organ disease caused becent study showed that CMV viraemia was still strongly associated with death in AIDS patients.onclusions: (1) CMV remains important in the era of HAART. (2) CMV has been underestimated as an important cofactor seginning of the AIDS epidemic.2005 Elsevier B.V. All rights reserved.

eywords: CMV; HIV; Cofactor; Pathogenesis; AIDS

. Introduction

Since the first cases of AIDS were defined in 1981, CMVnd organ disease has been an AIDS defining opportunistic

nfection. In this review, I will give a historical perspective touggest that throughout all of this time, including the currentra of highly active antiretroviral therapy (HAART), CMVas also acted as a cofactor, driving the pathogenicity of HIV. Iill particularly focus on new information which has becomevailable since I last reviewed this subject in 1998 (Griffiths,998).

.1. In vitro mechanisms

There are a variety of mechanisms which herpesvirusesuch as CMV could use to function as a cofactor, defined as

∗ Tel.: +44 20 7830 2997; fax: +44 20 7830 2854.E-mail address: [email protected].

“an infectious agent which interacts at the molecular orlular level to promote HIV pathogenicity” (Griffiths, 1992).These mechanisms are categorised inTable 1according towhether HIV and CMV infect the same or neighbourcells. The mechanisms are further illustrated inFig. 1a andb according to whether the net result is to activate HIV gexpression or to alter the tropism of HIV.

As illustrated inFig. 1a, CMV could activate latent provral HIV DNA by introducing its transactivator proteins inthe same cell (Davis et al., 1987). Alternatively, CMV couldreside in a bystander cell and release cytokines whichvate HIV latent provirus through signal transduction (Clouseet al., 1989). In the special case where HIV is latent in amemory cell whose cognate antigen receptor is specificCMV-encoded protein, CMV could release that antigen fa bystander cell so activating latent HIV provirus (Peterson eal., 1992) (Fig. 1a). Alternatively, as shown inFig. 1b CMVcould alter the tropism of HIV. If CMV infected the samcell which is producing HIV particles, then HIV could potetially form pseudotypes which would no longer be restric

386-6532/$ – see front matter © 2005 Elsevier B.V. All rights reserved.

oi:10.1016/j.jcv.2005.10.016
Page 2: CMV as a cofactor enhancing progression of AIDS

490 P.D. Griffiths / Journal of Clinical Virology 35 (2006) 489–492

Table 1Interactions between HIV and potential cofactor viruses

Effects of interaction HIV and cofactor virus infection

Same cell Neighbouring cells

Activate proviral HIV DNA Transactivation Cytokine releaseAntigen presentation

Alter tropism HIV RNA Pseudotype formation Up-regulation CD4 or co-receptorInduction alternative receptor

by the CD4 molecule and so would be able to bind to cellswhich contain receptors for CMV (Margalith et al., 1995).CMV has many glycoproteins which occur on the plasmamembrane and so could potentially take part in pseudotypeformation (Pignatelli et al., 2004). Alternatively, CMV couldactivate CD4 expression within cells which are CD4 negative(this has not been described in vitro for CMV but has beendescribed for HHV6 (Lusso et al., 1995)). The US28 gene ofCMV encodes a chemokine receptor which can substitute forCCR5, so permitting entry of HIV into CD4+ cells (Pleskoffet al., 1997). CMV could encode a molecule which can actas an alternative receptor for HIV; for example HIV coatedin non-neutralising antibodies can gain access to fibroblastsvia the CMV-encoded Fc receptor (McKeating et al., 1990)(Fig. 1b); an example of antibody-dependent enhancement ofinfectivity (Takada and Kawaoka, 2003).

1.2. Endpoints in vivo

The relationship between HIV and CMV is conventionallyconsidered according to the linear pattern shown inFig. 2.Thus, HIV progressively causes immune deficiency whichallows herpesviruses to reactivate in people with a low CD4count. Increasing herpesvirus replication then leads to a highherpesvirus viral load sufficient to cause opportunistic dis-e of

F ismsC

asymptomatic CMV viraemia at high viral load which pre-cedes the onset of end organ disease, usually CMV retinitis inAIDS patients (Bowen et al., 1997; Dodt et al., 1997; Shinkaiet al., 1997). In addition, CMV infection could potentiallyinteract with HIV using the circular pathway shown inFig. 2.Thus, CMV active infection could drive HIV replication tohigher levels (using some of the mechanisms described in thesection above) while the resulting HIV could in turn driveCMV replication setting up a vicious cycle with acceleratedprogression to AIDS. This might include driving the replica-tion of CMV to such a high level that it caused opportunisticdisease but this is not an essential component of the cofactorhypothesis which focuses on the circular pathway illustratedin Fig. 2. Thus, opportunistic disease caused by CMV maywell be distinct from the cofactor effect of CMV. CMV endorgan disease is thus not an appropriate end point to examinefor a putative cofactor effect, but progression to a new AIDSdefining condition, and to death, are appropriate. Since clini-cians focus on the opportunistic end organ disease caused byCMV, the putative asymptomatic CMV viraemia associatedwith the cofactor effect may be under-recognised. In the nextsection I will review the evidence from cohorts of patientswhich are consistent with this possibility and so support thehypothesis that CMV infection may be acting as a cofactor.

1

pos-i how ineds re oupo ta nex-p

ente nifi-

F tweenC

ase. This pattern is followed by CMV with a long period

ig. 1. (a) Mechanisms CMV could use to activate HIV. (b) MechanMV could use to alter the tropism of HIV.

.3. Studies in humans

In 1989 we reported that haemophiliacs who were serotive for CMV developed AIDS more rapidly than those were CMV seronegative and that this difference remaignificant once age was controlled for statistically (Webstet al., 1989a). We collaborated to study another large grf haemophiliacs but did not find a similar effect (Rabkin el., 1993); this difference between the studies remains ulained.

Detels et al. (1994)reported that patients with persistxcretion of CMV in serial samples of semen had a sig

ig. 2. Pathways leading to opportunistic vs. cofactor relationships beMV and HIV.

Page 3: CMV as a cofactor enhancing progression of AIDS

P.D. Griffiths / Journal of Clinical Virology 35 (2006) 489–492 491

cantly increased relative hazard of developing AIDS once dif-ferences in baseline CD4 counts were controlled statistically.

When studying the responses of patients with first episodeCMV retinitis to ganciclovir therapy using quantitative com-petitive PCR, we reported that those who presented witha CMV viral load higher than the median for the wholegroup had a significantly shorter survival than the remain-ing patients (Bowen et al., 1996). At that time, we couldnot be certain that this was not just an indirect measure ofHIV activity since HIV viral load measurements were notthen available. However, Steve Spector’s group answeredthis question in 1999 by showing that the death rate amongpatients enrolled in a randomised trial of oral ganciclovir wasdriven largely by the CMV viral load rather than the HIV viralload (Spector et al., 1999).

Also in 1999, Kovacs and colleagues reported on 440infants born to HIV positive mothers whose neonatal CMVstatus was known because of culture or serology results. HIVdisease was increased significantly amongst the children whowere positive for CMV. A raised HIV viral load was a riskfactor for disease progression only among the CMV seroneg-atives (Kovacs et al., 1999).

1.4. The cofactor effect in the era of HAART

The availability of HAART has dramatically controlledH no-c di Vv ctiveit ca-t itsa

int ntsg newA avee iteda 0 andf d theb plesf undt A.O sis-t MVp os-i endp keda otha

-upu IDSd NAl Vi h is

independent of CD4 count and HIV level; (ii) CD4 countand CMV DNA were persistently associated with mortalityand, once these two factors had been controlled, HIV viralload was no longer significant so showing that mortality isdriven by CMV and the CD4 count not by HIV(Deayton etal., 2004). Another group has recently reported that CMVviraemia is an important baseline variable associated withmortality (Jabs et al., 2005). Thus, CMV remains importantin the era of HAART.

The medical importance of these observations is that mor-tality could potentially be reduced by therapy directed againstCMV. My colleagues and I continue to propose that a ran-domised double-blind placebo controlled trial of anti-CMVtherapy should be conducted in AIDS patients with evidenceof CMV infection using mortality as the end point (Deaytonet al., 2004; Webster et al., 1989b). We are encouraged by not-ing that other investigators find that, although not randomisedto treatment groups, those who received systemic ganciclovirtherapy had a lower observed mortality than those who wereuntreated (Kempen et al., 2003).

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