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GB Virus Type C Coinfection in HIV-Infected African Mothers and Their Infants, KwaZulu Natal, South Africa
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Mahomed A. Sathar,1 Denis F. York,2 Eleanor Gouws,4 Anna Coutsoudis,3 and Hoosen M. Coovadia3
Departments of 1Medicine, 2Virology, and 3Paediatrics and Child Health, Nelson R. Mandela School of Medicine, Faculty of Health Sciences, University of Natal, and 4Centre of Epidemiological Research, Medical Research Council, Durban, South Africa
ABSTRACT/SUMMARY
GB virus type C (GBV-C) infection was studied in a convenience sample of 75 antiretroviral (ART) naive African mothers with human immunodeficiency virus infection and their infants.
GBV-C RNA was extracted from serum and amplified by reverse-transcriptase polymerase chain reaction. Twenty-seven (36%) of these 75 HIV-infected women tested positive for GBV-C RNA.
To study transmission dynamics, we chose a random subsample of 20 of these women and their infants. In this cohort, there was evidence of postnatal transmission of GBV-C; however, it was not possible to demonstrate evidence of in utero or intrapartum transmission.
In this pilot observational study, transmission of HIV from mother-to-infant occurs independently of the GBV-C infection status of the mother.
The immunological indices measured tend to suggest an association with protection and or delayed progression of HIV disease in GBV-C infected mothers.
Discussion by authors
The prevalence of GBV-C viremia in HIV-positive African mothers in this cohort (36%) is higher than that reported for healthy, immunocompetent African females (10%13%) but similar to that reported for HIV-infected, immunosuppressed persons in developed countries (14%-40%). GBV-C RNA was not detected in infants aged 1-6 weeks who were born to mothers who tested either positive or negative for GBV-C RNA. There does not appear to be any evidence that GBV-C is transmitted in utero and or intrapartum in this cohort. However, GBV-C vertical transmission rates of 10%-60% have been reported in newborns 15 days old.
The inability to detect GBV-C RNA 16 weeks after birth in the current cohort may have been due to lower GBV-C virus loads present in the early blood samples, which may have been below the detection limit of RT-PCR. Therefore, the possibility of in utero or intrapartum transmission of GBV-C cannot be ruled out. Two (11%) of 18 infants of mothers without GBV-C viremia had detectable levels of GBV-C RNA in serum samples obtained at 3 months of age. In contrast, GBV-C RNA was detected in 5% of infants (age, 5 months) born to HIV-negative African females with GBV-C viremia and in 2.9% of South African neonates <4 months of age.
Some infants acquire GBV-C from their infected mothers, as confirmed by the sequence data (our data not shown), possibly through contact with their mothers or through breast-feeding. However, to date, GBV-C RNA has not been detected in breast milk, and it is not clear whether transmission of GBV-C is influenced by breast-feeding or by the mode of delivery. Nor is it clear whether coinfection with HIV is the underlying cause for the MTCT of GBV-C.
Although GBV-C RNA has been detected in semen and saliva samples obtained from HIV-infected individuals, GBV-C replicative intermediaries have not been detected in salivary gland and gonad biopsy specimens obtained during autopsy of GBV-C RNApositive patients, which implies that the virus might be present in the saliva and semen of infected individuals but not transmitted by these routes. The presence of GBV-C RNA in body fluids other than serum implies that some infants may acquire infection by routes independent of MTCT (e.g., overcrowding may facilitate horizontal transmission) or by as yet unknown nonparenteral routes. It is interesting to note that, in the present cohort, 3 of 5 HIV-positive mothers with GBV-C viremia did not transmit HIV to their infants. In addition, Chakaraborty et al recently reported that 2 of 3 HIV-positive infants with GBV-C viremia were long-term survivors. It is difficult to make definitive conclusions about the role of GBV-C in the progression of HIV disease or its possible protective role in the vertical transmission of HIV, on the basis of small patient numbers. Although repeated testing of the samples gave identical results, the study is limited by the small sample size and the unavailability of serum samples from all patients at each of the sampling time points.
For the first time, relatively higher CD3 cell counts (due to an increase in T cell activity) and an increase in T cell expression, together with a decrease in CD30 cell counts (which reflects a decrease in activation status and an increase in T helper cell type 1 response) has been demonstrated in HIV-positive mothers with GBV-C viremia. These preliminary findings would tend to suggest an association between GBV-C and protection against and/or delayed progression of HIV disease in such patients. Although the mechanisms by which GBV-C interferes with HIV disease progression and death have not yet been clearly identified, there is evidence to suggest that GBV-C may have a direct inhibitory effect on HIV replication by the induction of chemokines; that it affects cytokine expression potentially apoptosis or HIV coreceptor down-regulationin vivo; that it alters cytokine expression and protects against THI to TH2 cytokine switching; and that it stimulates a strong anti-HIV cytolytic T cell response.
Human T cells possesses potent cytotoxic activity and are capable of producing a large array -chemokines and proinflammatory cytokines that are known to interfere with HIV replication. In humans, T cells are often found in increasing numbers during the course of several viral infections, and they seem to provide natural immunity at the early stages of the second virus infection by having a significant impact on virus replication. Significant alterations in the peripheral blood T cell activity occur in HIV-infected individuals, which is thought to be due to "superantigens/phosphoantigents" derived from bacteria, parasites, or viruses. CD30 cells are members of the TNF receptor family and, in terms of limiting viral responses, CD30 cells seem to act as "immune brakes". Recent studies, including our own, would tend to suggest that there may be multiple mechanisms by which GBV-C infection impairs HIV-associated disease progression and death. GBV-C coinfection may be a marker or stimulus for the presence of other unidentified factors associated with the slower progression of HIV infection.
In KwaZulu Natal, South Africa, HIV infection is pandemic, and ART is expensive and unavailable to the majority of HIV-infected persons. In such an environment, where the high prevalence of GBV-C is not associated with any clinical disease, the observational trends in our limited study warrants more-detailed investigations (in well-defined patient groups) of the possible "anti-HIV" effects associated with GBV-C. In resource-poor centers in Africa where the HIV pandemic is having a devastating effect, such studies may have an impact on new approaches to treat and/or prevent HIV infection and provide important insights on HIV pathogenesis that may be crucial for vaccine design before the intentional inoculating individuals with HIV infection with GBV-C.
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