- Email: [email protected]
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 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].
1386-6532/$ – see front matter © 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.jcv.2005.10.016
“an infectious agent which interacts at the molecular or cellular 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 proviral 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 activate 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 potentially form pseudotypes which would no longer be restricted
490
P.D. Griffiths / Journal of Clinical Virology 35 (2006) 489–492
Table 1 Interactions between HIV and potential cofactor viruses Effects of interaction
HIV and cofactor virus infection Same cell
Neighbouring cells
Activate proviral HIV DNA
Transactivation
Alter tropism HIV RNA
Pseudotype formation
Cytokine release Antigen presentation Up-regulation CD4 or co-receptor Induction alternative receptor
by the CD4 molecule and so would be able to bind to cells which contain receptors for CMV (Margalith et al., 1995). CMV has many glycoproteins which occur on the plasma membrane and so could potentially take part in pseudotype formation (Pignatelli et al., 2004). Alternatively, CMV could activate CD4 expression within cells which are CD4 negative (this has not been described in vitro for CMV but has been described for HHV6 (Lusso et al., 1995)). The US28 gene of CMV encodes a chemokine receptor which can substitute for CCR5, so permitting entry of HIV into CD4+ cells (Pleskoff et al., 1997). CMV could encode a molecule which can act as an alternative receptor for HIV; for example HIV coated in non-neutralising antibodies can gain access to fibroblasts via the CMV-encoded Fc receptor (McKeating et al., 1990) (Fig. 1b); an example of antibody-dependent enhancement of infectivity (Takada and Kawaoka, 2003). 1.2. Endpoints in vivo The relationship between HIV and CMV is conventionally considered according to the linear pattern shown in Fig. 2. Thus, HIV progressively causes immune deficiency which allows herpesviruses to reactivate in people with a low CD4 count. Increasing herpesvirus replication then leads to a high herpesvirus viral load sufficient to cause opportunistic disease. This pattern is followed by CMV with a long period of
asymptomatic CMV viraemia at high viral load which precedes the onset of end organ disease, usually CMV retinitis in AIDS patients (Bowen et al., 1997; Dodt et al., 1997; Shinkai et al., 1997). In addition, CMV infection could potentially interact with HIV using the circular pathway shown in Fig. 2. Thus, CMV active infection could drive HIV replication to higher levels (using some of the mechanisms described in the section above) while the resulting HIV could in turn drive CMV replication setting up a vicious cycle with accelerated progression to AIDS. This might include driving the replication of CMV to such a high level that it caused opportunistic disease but this is not an essential component of the cofactor hypothesis which focuses on the circular pathway illustrated in Fig. 2. Thus, opportunistic disease caused by CMV may well be distinct from the cofactor effect of CMV. CMV end organ disease is thus not an appropriate end point to examine for a putative cofactor effect, but progression to a new AIDS defining condition, and to death, are appropriate. Since clinicians focus on the opportunistic end organ disease caused by CMV, the putative asymptomatic CMV viraemia associated with the cofactor effect may be under-recognised. In the next section I will review the evidence from cohorts of patients which are consistent with this possibility and so support the hypothesis that CMV infection may be acting as a cofactor. 1.3. Studies in humans In 1989 we reported that haemophiliacs who were seropositive for CMV developed AIDS more rapidly than those who were CMV seronegative and that this difference remained significant once age was controlled for statistically (Webster et al., 1989a). We collaborated to study another large group of haemophiliacs but did not find a similar effect (Rabkin et al., 1993); this difference between the studies remains unexplained. Detels et al. (1994) reported that patients with persistent excretion of CMV in serial samples of semen had a signifi-
Fig. 1. (a) Mechanisms CMV could use to activate HIV. (b) Mechanisms CMV could use to alter the tropism of HIV.
Fig. 2. Pathways leading to opportunistic vs. cofactor relationships between CMV and HIV.
P.D. Griffiths / Journal of Clinical Virology 35 (2006) 489–492
cantly increased relative hazard of developing AIDS once differences in baseline CD4 counts were controlled statistically. When studying the responses of patients with first episode CMV retinitis to ganciclovir therapy using quantitative competitive PCR, we reported that those who presented with a CMV viral load higher than the median for the whole group had a significantly shorter survival than the remaining patients (Bowen et al., 1996). At that time, we could not be certain that this was not just an indirect measure of HIV activity since HIV viral load measurements were not then available. However, Steve Spector’s group answered this question in 1999 by showing that the death rate among patients enrolled in a randomised trial of oral ganciclovir was driven largely by the CMV viral load rather than the HIV viral load (Spector et al., 1999). Also in 1999, Kovacs and colleagues reported on 440 infants born to HIV positive mothers whose neonatal CMV status was known because of culture or serology results. HIV disease was increased significantly amongst the children who were positive for CMV. A raised HIV viral load was a risk factor for disease progression only among the CMV seronegatives (Kovacs et al., 1999). 1.4. The cofactor effect in the era of HAART The availability of HAART has dramatically controlled HIV replication, so delaying the development of immunocompromise (Palella et al., 1998). In addition, we showed in 1999 that HAART also reduced asymptomatic CMV viraemia, presumably because HAART gave back protective immune functions against CMV (Deayton et al., 1999). Thus, the availability of HAART has both decreased HIV replication and the replication of CMV so potentially impairing its ability to act as a cofactor. To determine if CMV still has a cofactor role to play in the era of HAART we decided to follow a cohort of patients given HAART and observe if those who progress to new AIDS defining conditions or to death were more likely to have evidence of CMV infection than the remainder. We recruited any patient whose CD4 count had ever been less than 100 and followed them for a median of 36 months as they received the best available HAART therapy. We collected blood samples for CMV PCR whenever they attended the clinic and found that 375/2969 (13%) of these were positive for CMV DNA. Of the 374 patients who were followed, 69% were consistently CMV negative throughout, 4% were consistently CMV positive and 27% of patients were intermittently CMV positive or negative. We examined the group for the two end points of new AIDS defining conditions or death and looked at CMV, CD4 counts and HIV viral load as covariates both at baseline and time updated (Deayton et al., 2004). To summarise the covariates measured over follow-up using multivariable analyses: (i) progression to a new AIDS defining event was significantly associated with HIV RNA level, CD4 count and CMV DNA thus showing that CMV is an additional risk factor for disease progression which is
491
independent of CD4 count and HIV level; (ii) CD4 count and CMV DNA were persistently associated with mortality and, once these two factors had been controlled, HIV viral load was no longer significant so showing that mortality is driven by CMV and the CD4 count not by HIV(Deayton et al., 2004). Another group has recently reported that CMV viraemia is an important baseline variable associated with mortality (Jabs et al., 2005). Thus, CMV remains important in the era of HAART. The medical importance of these observations is that mortality could potentially be reduced by therapy directed against CMV. My colleagues and I continue to propose that a randomised double-blind placebo controlled trial of anti-CMV therapy should be conducted in AIDS patients with evidence of CMV infection using mortality as the end point (Deayton et al., 2004; Webster et al., 1989b). We are encouraged by noting that other investigators find that, although not randomised to treatment groups, those who received systemic ganciclovir therapy had a lower observed mortality than those who were untreated (Kempen et al., 2003).
References Bowen EF, Sabin CA, Wilson P, Griffiths PD, Davey CC, Johnson MA, Emery VC. Cytomegalovirus (CMV) viraemia detected by polymerase chain reaction identifies a group of HIV-positive patients at high risk of CMV disease. AIDS 1997;11:889–93. Bowen EF, Wilson P, Cope A, Sabin C, Griffiths P, Davey C, Johnson M, Emery V. Cytomegalovirus retinitis in AIDS patients: influence of cytomegaloviral load on response to ganciclovir, time to recurrence and survival. AIDS 1996;10:1515–20. Clouse KA, Robbins PB, Fernie B, Ostrove JM, Fauci AS. Viral antigen stimulation of the production of human monokines capable of regulating HIV1 expression. J Immunol 1989;143:470–5. Davis MG, Kenney SC, Kamine J, Pagano JS, Huang ES. Immediateearly gene region of human cytomegalovirus trans-activates the promoter of human immunodeficiency virus. Proc Natl Acad Sci USA 1987;84:8642–6. Deayton J, Mocroft A, Wilson P, Emery VC, Johnson MA, Griffiths PD. Loss of cytomegalovirus (CMV) viraemia following highly active antiretroviral therapy in the absence of specific anti-CMV therapy. AIDS 1999;13:1203–6. Deayton JR, Prof Sabin CA, Johnson MA, Emery VC, Wilson P, Griffiths PD. Importance of cytomegalovirus viraemia in risk of disease progression and death in HIV-infected patients receiving highly active antiretroviral therapy. Lancet 2004;363:2116–21. Detels R, Leach CT, Hennessey K, Liu Z, Visscher BR, Cherry JD, Giorgi JV. Persistent cytomegalovirus infection of semen increases risk of AIDS. J Infect Dis 1994;169:766–8. Dodt KK, Jacobsen PH, Hofmann B, Meyer C, Kolmos HJ, Skinhoj P, Norrild B, Mathiesen L. Development of cytomegalovirus (CMV) disease may be predicted in HIV-infected patients by CMV polymerase chain reaction and the antigenemia test. AIDS 1997;11:F21–8. Griffiths PD. Studies to define viral cofactors for human immunodeficiency virus. Infect Agents Dis 1992;1:237–44. Griffiths PD. Studies of viral cofactors for human immunodeficiency virus in vitro and in vivo. J Gen Virol 1998;79(Pt 2):213–20. Jabs DA, Holbrook JT, Van Natta ML, Clark R, Jacobson MA, Kempen JH, Murphy RL. Risk factors for mortality in patients with AIDS in the era of highly active antiretroviral therapy. Ophthalmology 2005;112:771–9.
492
P.D. Griffiths / Journal of Clinical Virology 35 (2006) 489–492
Kempen JH, Jabs DA, Wilson LA, Dunn JP, West SK, Tonascia J. Mortality risk for patients with cytomegalovirus retinitis and acquired immune deficiency syndrome. Clin Infect Dis 2003;37:1365–73. Kovacs A, Schluchter M, Easley K, Demmler G, Shearer W, La Russa P, Pitt J, Cooper E, Goldfarb J, Hodes D, Kattan M, McIntosh K. Cytomegalovirus infection and HIV-1 disease progression in infants born to HIV-1-infected women Pediatric Pulmonary and Cardiovascular Complications of Vertically Transmitted HIV Infection Study Group. N Engl J Med 1999;341:77–84. Lusso P, Garzino-Demo A, Crowley RW, Malnati MS. Infection of gamma/delta T lymphocytes by human herpesvirus 6: transcriptional induction of CD4 and susceptibility to HIV infection. J Exp Med 1995;181:1303–10. Margalith M, D’Aquila RT, Manion DJ, Basgoz N, Bechtel LJ, Smith BR, Kaplan JC, Hirsch MS. HIV-1 DNA in fibroblast cultures infected with urine from HIV-seropositive cytomegalovirus (CMV) excretors. Arch Virol 1995;140:927–35. McKeating JA, Griffiths PD, Weiss RA. HIV susceptibility conferred to human fibroblasts by cytomegalovirus-induced Fc receptor. Nature 1990;343:659–61. Palella Jr FJ, Delaney KM, Moorman AC, Loveless MO, Fuhrer J, Satten GA, Aschman DJ, Holmberg SD. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection HIV outpatient study investigators. N Engl J Med 1998;338:853–60. Peterson PK, Gekker G, Chao CC, Hu SX, Edelman C, Balfour Jr HH, Verhoef J. Human cytomegalovirus-stimulated peripheral blood mononuclear cells induce HIV-1 replication via a tumor necrosis factor-alpha-mediated mechanism. J Clin Invest 1992;89:574–80.
Pignatelli S, Dal Monte P, Rossini G, Landini MP. Genetic polymorphisms among human cytomegalovirus (HCMV) wild-type strains. Rev Med Virol 2004;14:383–410. Pleskoff O, Treboute C, Brelot A, Heveker N, Seman M, Alizon M. Identification of a chemokine receptor encoded by human cytomegalovirus as a cofactor for HIV-1 entry. Science 1997;276:1874–8. Rabkin CS, Hatzakis A, Griffiths PD, Pillay D, Ragni MV, Hilgartner MW, Goedert JJ. Cytomegalovirus infection and risk of AIDS in human immunodeficiency virus-infected hemophilia patients National Cancer Institute Multicenter Hemophilia Cohort Study Group. J Infect Dis 1993;168:1260–3. Shinkai M, Bozzette SA, Powderly W, Frame P, Spector SA. Utility of urine and leukocyte cultures and plasma DNA polymerase chain reaction for identification of AIDS patients at risk for developing human cytomegalovirus disease. J Infect Dis 1997;175:302–8. Spector SA, Hsia K, Crager M, Pilcher M, Cabral S, Stempien MJ. Cytomegalovirus (CMV) DNA load is an independent predictor of CMV disease and survival in advanced AIDS. J Virol 1999;73:7027–30. Takada A, Kawaoka Y. Antibody-dependent enhancement of viral infection: molecular mechanisms and in vivo implications. Rev Med Virol 2003;13:387–98. Webster A, Grundy JE, Lee CA, Emery VC, Cook DG, Kernoff PB, Griffiths PD. Cytomegalovirus infection and progression to AIDS. Lancet 1989a;2:681. Webster A, Lee CA, Cook DG, Grundy JE, Emery VC, Kernoff PB, Griffiths PD. Cytomegalovirus infection and progression towards AIDS in haemophiliacs with human immunodeficiency virus infection. Lancet 1989b;2:63–6.
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].
1386-6532/$ – see front matter © 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.jcv.2005.10.016
“an infectious agent which interacts at the molecular or cellular 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 proviral 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 activate 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 potentially form pseudotypes which would no longer be restricted
490
P.D. Griffiths / Journal of Clinical Virology 35 (2006) 489–492
Table 1 Interactions between HIV and potential cofactor viruses Effects of interaction
HIV and cofactor virus infection Same cell
Neighbouring cells
Activate proviral HIV DNA
Transactivation
Alter tropism HIV RNA
Pseudotype formation
Cytokine release Antigen presentation Up-regulation CD4 or co-receptor Induction alternative receptor
by the CD4 molecule and so would be able to bind to cells which contain receptors for CMV (Margalith et al., 1995). CMV has many glycoproteins which occur on the plasma membrane and so could potentially take part in pseudotype formation (Pignatelli et al., 2004). Alternatively, CMV could activate CD4 expression within cells which are CD4 negative (this has not been described in vitro for CMV but has been described for HHV6 (Lusso et al., 1995)). The US28 gene of CMV encodes a chemokine receptor which can substitute for CCR5, so permitting entry of HIV into CD4+ cells (Pleskoff et al., 1997). CMV could encode a molecule which can act as an alternative receptor for HIV; for example HIV coated in non-neutralising antibodies can gain access to fibroblasts via the CMV-encoded Fc receptor (McKeating et al., 1990) (Fig. 1b); an example of antibody-dependent enhancement of infectivity (Takada and Kawaoka, 2003). 1.2. Endpoints in vivo The relationship between HIV and CMV is conventionally considered according to the linear pattern shown in Fig. 2. Thus, HIV progressively causes immune deficiency which allows herpesviruses to reactivate in people with a low CD4 count. Increasing herpesvirus replication then leads to a high herpesvirus viral load sufficient to cause opportunistic disease. This pattern is followed by CMV with a long period of
asymptomatic CMV viraemia at high viral load which precedes the onset of end organ disease, usually CMV retinitis in AIDS patients (Bowen et al., 1997; Dodt et al., 1997; Shinkai et al., 1997). In addition, CMV infection could potentially interact with HIV using the circular pathway shown in Fig. 2. Thus, CMV active infection could drive HIV replication to higher levels (using some of the mechanisms described in the section above) while the resulting HIV could in turn drive CMV replication setting up a vicious cycle with accelerated progression to AIDS. This might include driving the replication of CMV to such a high level that it caused opportunistic disease but this is not an essential component of the cofactor hypothesis which focuses on the circular pathway illustrated in Fig. 2. Thus, opportunistic disease caused by CMV may well be distinct from the cofactor effect of CMV. CMV end organ disease is thus not an appropriate end point to examine for a putative cofactor effect, but progression to a new AIDS defining condition, and to death, are appropriate. Since clinicians focus on the opportunistic end organ disease caused by CMV, the putative asymptomatic CMV viraemia associated with the cofactor effect may be under-recognised. In the next section I will review the evidence from cohorts of patients which are consistent with this possibility and so support the hypothesis that CMV infection may be acting as a cofactor. 1.3. Studies in humans In 1989 we reported that haemophiliacs who were seropositive for CMV developed AIDS more rapidly than those who were CMV seronegative and that this difference remained significant once age was controlled for statistically (Webster et al., 1989a). We collaborated to study another large group of haemophiliacs but did not find a similar effect (Rabkin et al., 1993); this difference between the studies remains unexplained. Detels et al. (1994) reported that patients with persistent excretion of CMV in serial samples of semen had a signifi-
Fig. 1. (a) Mechanisms CMV could use to activate HIV. (b) Mechanisms CMV could use to alter the tropism of HIV.
Fig. 2. Pathways leading to opportunistic vs. cofactor relationships between CMV and HIV.
P.D. Griffiths / Journal of Clinical Virology 35 (2006) 489–492
cantly increased relative hazard of developing AIDS once differences in baseline CD4 counts were controlled statistically. When studying the responses of patients with first episode CMV retinitis to ganciclovir therapy using quantitative competitive PCR, we reported that those who presented with a CMV viral load higher than the median for the whole group had a significantly shorter survival than the remaining patients (Bowen et al., 1996). At that time, we could not be certain that this was not just an indirect measure of HIV activity since HIV viral load measurements were not then available. However, Steve Spector’s group answered this question in 1999 by showing that the death rate among patients enrolled in a randomised trial of oral ganciclovir was driven largely by the CMV viral load rather than the HIV viral load (Spector et al., 1999). Also in 1999, Kovacs and colleagues reported on 440 infants born to HIV positive mothers whose neonatal CMV status was known because of culture or serology results. HIV disease was increased significantly amongst the children who were positive for CMV. A raised HIV viral load was a risk factor for disease progression only among the CMV seronegatives (Kovacs et al., 1999). 1.4. The cofactor effect in the era of HAART The availability of HAART has dramatically controlled HIV replication, so delaying the development of immunocompromise (Palella et al., 1998). In addition, we showed in 1999 that HAART also reduced asymptomatic CMV viraemia, presumably because HAART gave back protective immune functions against CMV (Deayton et al., 1999). Thus, the availability of HAART has both decreased HIV replication and the replication of CMV so potentially impairing its ability to act as a cofactor. To determine if CMV still has a cofactor role to play in the era of HAART we decided to follow a cohort of patients given HAART and observe if those who progress to new AIDS defining conditions or to death were more likely to have evidence of CMV infection than the remainder. We recruited any patient whose CD4 count had ever been less than 100 and followed them for a median of 36 months as they received the best available HAART therapy. We collected blood samples for CMV PCR whenever they attended the clinic and found that 375/2969 (13%) of these were positive for CMV DNA. Of the 374 patients who were followed, 69% were consistently CMV negative throughout, 4% were consistently CMV positive and 27% of patients were intermittently CMV positive or negative. We examined the group for the two end points of new AIDS defining conditions or death and looked at CMV, CD4 counts and HIV viral load as covariates both at baseline and time updated (Deayton et al., 2004). To summarise the covariates measured over follow-up using multivariable analyses: (i) progression to a new AIDS defining event was significantly associated with HIV RNA level, CD4 count and CMV DNA thus showing that CMV is an additional risk factor for disease progression which is
491
independent of CD4 count and HIV level; (ii) CD4 count and CMV DNA were persistently associated with mortality and, once these two factors had been controlled, HIV viral load was no longer significant so showing that mortality is driven by CMV and the CD4 count not by HIV(Deayton et al., 2004). Another group has recently reported that CMV viraemia is an important baseline variable associated with mortality (Jabs et al., 2005). Thus, CMV remains important in the era of HAART. The medical importance of these observations is that mortality could potentially be reduced by therapy directed against CMV. My colleagues and I continue to propose that a randomised double-blind placebo controlled trial of anti-CMV therapy should be conducted in AIDS patients with evidence of CMV infection using mortality as the end point (Deayton et al., 2004; Webster et al., 1989b). We are encouraged by noting that other investigators find that, although not randomised to treatment groups, those who received systemic ganciclovir therapy had a lower observed mortality than those who were untreated (Kempen et al., 2003).
References Bowen EF, Sabin CA, Wilson P, Griffiths PD, Davey CC, Johnson MA, Emery VC. Cytomegalovirus (CMV) viraemia detected by polymerase chain reaction identifies a group of HIV-positive patients at high risk of CMV disease. AIDS 1997;11:889–93. Bowen EF, Wilson P, Cope A, Sabin C, Griffiths P, Davey C, Johnson M, Emery V. Cytomegalovirus retinitis in AIDS patients: influence of cytomegaloviral load on response to ganciclovir, time to recurrence and survival. AIDS 1996;10:1515–20. Clouse KA, Robbins PB, Fernie B, Ostrove JM, Fauci AS. Viral antigen stimulation of the production of human monokines capable of regulating HIV1 expression. J Immunol 1989;143:470–5. Davis MG, Kenney SC, Kamine J, Pagano JS, Huang ES. Immediateearly gene region of human cytomegalovirus trans-activates the promoter of human immunodeficiency virus. Proc Natl Acad Sci USA 1987;84:8642–6. Deayton J, Mocroft A, Wilson P, Emery VC, Johnson MA, Griffiths PD. Loss of cytomegalovirus (CMV) viraemia following highly active antiretroviral therapy in the absence of specific anti-CMV therapy. AIDS 1999;13:1203–6. Deayton JR, Prof Sabin CA, Johnson MA, Emery VC, Wilson P, Griffiths PD. Importance of cytomegalovirus viraemia in risk of disease progression and death in HIV-infected patients receiving highly active antiretroviral therapy. Lancet 2004;363:2116–21. Detels R, Leach CT, Hennessey K, Liu Z, Visscher BR, Cherry JD, Giorgi JV. Persistent cytomegalovirus infection of semen increases risk of AIDS. J Infect Dis 1994;169:766–8. Dodt KK, Jacobsen PH, Hofmann B, Meyer C, Kolmos HJ, Skinhoj P, Norrild B, Mathiesen L. Development of cytomegalovirus (CMV) disease may be predicted in HIV-infected patients by CMV polymerase chain reaction and the antigenemia test. AIDS 1997;11:F21–8. Griffiths PD. Studies to define viral cofactors for human immunodeficiency virus. Infect Agents Dis 1992;1:237–44. Griffiths PD. Studies of viral cofactors for human immunodeficiency virus in vitro and in vivo. J Gen Virol 1998;79(Pt 2):213–20. Jabs DA, Holbrook JT, Van Natta ML, Clark R, Jacobson MA, Kempen JH, Murphy RL. Risk factors for mortality in patients with AIDS in the era of highly active antiretroviral therapy. Ophthalmology 2005;112:771–9.
492
P.D. Griffiths / Journal of Clinical Virology 35 (2006) 489–492
Kempen JH, Jabs DA, Wilson LA, Dunn JP, West SK, Tonascia J. Mortality risk for patients with cytomegalovirus retinitis and acquired immune deficiency syndrome. Clin Infect Dis 2003;37:1365–73. Kovacs A, Schluchter M, Easley K, Demmler G, Shearer W, La Russa P, Pitt J, Cooper E, Goldfarb J, Hodes D, Kattan M, McIntosh K. Cytomegalovirus infection and HIV-1 disease progression in infants born to HIV-1-infected women Pediatric Pulmonary and Cardiovascular Complications of Vertically Transmitted HIV Infection Study Group. N Engl J Med 1999;341:77–84. Lusso P, Garzino-Demo A, Crowley RW, Malnati MS. Infection of gamma/delta T lymphocytes by human herpesvirus 6: transcriptional induction of CD4 and susceptibility to HIV infection. J Exp Med 1995;181:1303–10. Margalith M, D’Aquila RT, Manion DJ, Basgoz N, Bechtel LJ, Smith BR, Kaplan JC, Hirsch MS. HIV-1 DNA in fibroblast cultures infected with urine from HIV-seropositive cytomegalovirus (CMV) excretors. Arch Virol 1995;140:927–35. McKeating JA, Griffiths PD, Weiss RA. HIV susceptibility conferred to human fibroblasts by cytomegalovirus-induced Fc receptor. Nature 1990;343:659–61. Palella Jr FJ, Delaney KM, Moorman AC, Loveless MO, Fuhrer J, Satten GA, Aschman DJ, Holmberg SD. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection HIV outpatient study investigators. N Engl J Med 1998;338:853–60. Peterson PK, Gekker G, Chao CC, Hu SX, Edelman C, Balfour Jr HH, Verhoef J. Human cytomegalovirus-stimulated peripheral blood mononuclear cells induce HIV-1 replication via a tumor necrosis factor-alpha-mediated mechanism. J Clin Invest 1992;89:574–80.
Pignatelli S, Dal Monte P, Rossini G, Landini MP. Genetic polymorphisms among human cytomegalovirus (HCMV) wild-type strains. Rev Med Virol 2004;14:383–410. Pleskoff O, Treboute C, Brelot A, Heveker N, Seman M, Alizon M. Identification of a chemokine receptor encoded by human cytomegalovirus as a cofactor for HIV-1 entry. Science 1997;276:1874–8. Rabkin CS, Hatzakis A, Griffiths PD, Pillay D, Ragni MV, Hilgartner MW, Goedert JJ. Cytomegalovirus infection and risk of AIDS in human immunodeficiency virus-infected hemophilia patients National Cancer Institute Multicenter Hemophilia Cohort Study Group. J Infect Dis 1993;168:1260–3. Shinkai M, Bozzette SA, Powderly W, Frame P, Spector SA. Utility of urine and leukocyte cultures and plasma DNA polymerase chain reaction for identification of AIDS patients at risk for developing human cytomegalovirus disease. J Infect Dis 1997;175:302–8. Spector SA, Hsia K, Crager M, Pilcher M, Cabral S, Stempien MJ. Cytomegalovirus (CMV) DNA load is an independent predictor of CMV disease and survival in advanced AIDS. J Virol 1999;73:7027–30. Takada A, Kawaoka Y. Antibody-dependent enhancement of viral infection: molecular mechanisms and in vivo implications. Rev Med Virol 2003;13:387–98. Webster A, Grundy JE, Lee CA, Emery VC, Cook DG, Kernoff PB, Griffiths PD. Cytomegalovirus infection and progression to AIDS. Lancet 1989a;2:681. Webster A, Lee CA, Cook DG, Grundy JE, Emery VC, Kernoff PB, Griffiths PD. Cytomegalovirus infection and progression towards AIDS in haemophiliacs with human immunodeficiency virus infection. Lancet 1989b;2:63–6.