Since the beginning of the global HIV epidemic, intercurrent infection with human cytomegalovirus (CMV) has commanded considerable attention. Indeed, prior to the discovery of HIV, the ubiquitous presence of CMV infection in Kaposi Sarcoma patients suggested that CMV may have a causal association with AIDS . As more was learned about the natural history of HIV infection, CMV clearly emerged as a major opportunistic pathogen, causing sight-threatening and occasionally life-threatening disease in patients with advanced AIDS. Moreover, CMV infection has been shown in a number of studies to accelerate progression of HIV infection. The era of HAART therapy has greatly reduced the risk of CMV disease in HIV-infected individuals, but much remains to be learned about the precise nature of HIV–CMV interactions. A better understanding of how these two viruses interact could in turn have implications for evolving antiviral and vaccine strategies.
Toward this goal, the important paper by Slyker et al. in this issue of AIDS addresses HIV–CMV interaction in a vulnerable and understudied patient population: the congenitally infected infant. This study represents a longitudinal description of CMV plasma viral loads during acute infection in HIV-infected and HIV-exposed (but uninfected) Kenyan infants. The incidence of CMV infection was remarkably high in infants born to HIV-infected women, with more than 90% infected by 1 year of age, regardless of the ultimate HIV-1 status of the infant. Of interest was the duration of DNAemia, both in HIV infected and HIV uninfected infants. CMV DNA continued to be detected in the plasma for many months after the first detection of CMV infection. CMV was detected in 75% of HIV-exposed uninfected infants and in 50% of HIV-infected infants tested at 12 months post CMV infection. This is in contrast to what is observed in adult patients, who typically clear DNAemia within 6 months postinfection.
These data reinforce observations made in the United States cohorts, where CMV coinfection has been noted in up to 40% of HIV-infected infants during the first year of life, and is associated with an approximate 2.5-fold increased risk of disease progression [3,4]. The novel insight provided by Slyker et al.  is based on the longitudinal nature of the virological follow-up in these infants, in particular the finding of long-term CMV DNAemia. These observations provide potential insight into viral interactions during acute HIV-1/CMV coinfection. There was a strong correlation between peak HIV-1 and CMV viral loads. Although the presence of HIV infection in CMV-infected infants did not appear to impact the magnitude of CMV DNAemia, it is noteworthy that HIV-infected infants had a greater magnitude of DNAemia, with significantly higher peak CMV loads than HIV-exposed uninfected infants. There was also a trend for more rapid reduction of CMV viral load in the HIV-exposed, but uninfected, infants compared to HIV-infected infants. Congenital HIV infection also significantly increased the risk of having congenital CMV infection. CMV DNA was detected in cord blood plasma of 29% (4/14) of HIV-infected newborns compared to only 2.7% (1/37) of infants who were HIV-1 RNA negative at birth. Together, these data indicate: congenital HIV infection increases the risk for congenital CMV infection; infants born to HIV-infected women experience a remarkably high rate of CMV infection in early life; CMV DNAemia is present for an extended period of time in both HIV-exposed and HIV-infected infants with congenital CMV infection; and HIV-infection appears to impair containment of CMV replication, as evidenced by higher viral CMV viral loads.
These observations have implications not only for an improved understanding of HIV–CMV interactions, but also an improved understanding of the dynamics of CMV replication and clearance in the HIV-uninfected infant. The factors that affect the duration of DNAemia in infants with congenital or perinatal CMV infection in the absence of HIV are incompletely understood, but the magnitude and duration of DNAemia may be important risk factors for the development of neurodevelopmental sequelae [5–8]. It is unclear if the magnitude and duration of DNAemia in CMV-infected, HIV-uninfected infants in the Slyker study is different than that which has been observed in congenital or perinatally acquired CMV infection in the developed world. Conceivably, the higher CMV viral load that would be anticipated in the HIV-infected woman could in turn predispose to high viral loads in the congenitally or perinatally infected infant with CMV, even in the absence of vertical HIV transmission. This in turn could predispose the infant in this setting to an increased risk of symptomatic disease, and may identify infants who could benefit from anti-CMV therapies, as resources permit. Future studies should attempt to define if maternal HIV infection is a risk factor for higher CMV viral loads in HIV-uninfected infants who acquire CMV infection in utero or in the early postnatal period, compared to infants with congenital and perinatal CMV infections born to HIV-negative women. Although Slyker et al.  report that no infants in their study cohort had symptomatic congenital CMV infection; data from serial audiological examinations are not reported (presumably because this information could not be collected in a resource-poor environment). Valuable information about hearing-related outcomes could be an important aspect of future studies in this population, since sensorineural hearing loss is the major disability associated with congenital CMV infection.
Another fruitful area for future study in this patient population would be an assessment of the ontogeny and specificity of the CD4+ response to CMV. In otherwise immunocompetent infants infected early in infancy, persistent viral shedding in urine has been shown to be associated with a delayed CD4+ response, and this persistent and selective deficiency of CD4+ T-cell immunity to CMV is unique to young children, not being observed in adults with primary infection . It is possible that the impairment of CD4+ responses induced by intercurrent HIV infection plays a role in the persistent and slowly resolving DNAemia observed by Slyker et al. In congenitally and perinatally CMV-infected infants, early CD8+ responses are of focused peptide specificity and low peptide avidity , and investigation of potential perturbation of the CD8+ response in the setting of coincident HIV infection also merits consideration. Although Slyker et al.  focused their analysis on how HIV infection might impair CMV clearance, CMV DNAemia may well fan the flames of HIV replication as well. CMV infection dominates the memory compartment in the chronically infected individual, with approximately 10% of both CD4+ and CD8+ memory cells being devoted to control of CMV . The extensive T-cell resources devoted to controlling CMV have been cited as an explanation for CMV-induced ‘immunosenescence’ , a phenomena that may slowly evolve over the lifetime of the infected host. The extent to which congenital or perinatally acquired CMV infections may be immunosuppressive, or may promote progression of HIV or other chronic infections, requires further investigation.
As Slyker et al. propose, these finding may have implications for CMV disease control strategies, such as vaccination, that may in turn help control HIV disease in sub-Saharan Africa. CMV vaccines are a major public health priority, and the burden of disease caused by congenital CMV infection in the developing world is sorely understudied. A word of caution should be interjected, however. Most of the CMV infections described in the Kenyan cohort were not acquired congenitally, but postnatally, via breast-feeding. It is not clear to what extent, if any, CMV would produce morbidity when transmitted in this fashion. Clearly, acquisition of CMV via breast milk is a health risk in low-birth weight premature infants, but the health consequences for term babies appear minimal. More information is needed, however, about neurodevelopmental status, particularly with respect to hearing, in breast milk-acquired CMV infections in infancy . Although HIV infection clearly modifies the clearance of CMV infections even when CMV is postnatally acquired , the adverse health consequences of acquiring CMV infections in infancy require clarification in future studies. Moreover, it is not clear what role vaccination might play in reducing acquisition of CMV in this setting, or whether any immunization strategy could prevent breast milk-acquired CMV infections. In the developing world, the delicate balance of the salutary effects of breast-feeding versus the risks of acquiring viral infection from breast milk needs to be considered not only in the context of HIV transmission, but CMV transmission as well. How these viruses might interact with immunological components in human milk is also a very high priority area for future clinical and immunological research.
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