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GB Virus Type C Coinfection in HIV-Infected African Mothers and Their Infants, KwaZulu Natal, South Africa

  1. Mahomed A. Sathar1,
  2. Denis F. York2,
  3. Eleanor Gouws4,
  4. Anna Coutsoudis3, and
  5. Hoosen M. Coovadia3
  1. 1Department of Medicine, University of Natal, Durban, South Africa
  2. 2Department of Virology, University of Natal, Durban, South Africa
  3. 3Department of Paediatrics and Child Health, Nelson R. Mandela School of Medicine, Faculty of Health Sciences, University of Natal, Durban, South Africa
  4. 4Centre of Epidemiological Research, Medical Research Council, Durban, South Africa
  1. Reprints or correspondence: Dr. M. A. Sathar, Dept. of Medicine, Nelson R. Mandela School of Medicine, Faculty of Health Sciences, PO Box 7, Congella, Durban, South Africa 4013 (sathar{at}nu.ac.za).
 
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Abstract

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.

In the province of KwaZulu Natal, South Africa, the HIV pandemic and the consequent development of AIDS poses an enormous threat to the socioeconomic and political landscape of this province [1]. Official South African Department of Health figures compiled from antenatal clinics across the country show a significant increase in the infection rate among pregnant women in most provinces, with the highest figures (33%) reported in KwaZulu Natal [1, 2]. The majority (70%) of HIV-infected individuals living in sub-Saharan Africa cannot afford antiretroviral therapy (ART) [3]. Despite administration of short-course ART for the prevention of mother-to-child transmission (MTCT) of HIV, transmission at antepartum (7%) and through breast-feeding (4%) remains high [3, 4]. It is estimated that, worldwide, >600,000 children per annum become infected with HIV through MTCT, with between one-third and one-half of these infections acquired through breast-feeding [5].

Viral coinfections with HIV acquired pre- or postnatally are generally deleterious [6, 7]. Most studies to date have reported that, in HIV-positive adults, GB virus type C (GBV-C; also referred to as hepatitis G virus) slows down the progression to AIDS and associated death [8, 9]. It is unclear whether the apparent protective effect of GBV-C is due to host immune modulation—a direct effect of HIV infectivity or replication—or to GBV-C itself [8, 9]. However, GBV-C coinfection may be a marker for the presence of other unidentified factors associated with the slower progression of HIV infection [9, 10]. In KwaZulu Natal, the epicenter of the HIV pandemic, GBV-C infection is common and is not associated with any clinical disease [11].

In HIV-negative South African blood donors and random populations, the prevalence of GBV-C RNA (10%–20%) parallels the prevalence of antibody to envelope protein E2 (anti-E2; 12%–20%) [11,12]. This is similar to the prevalence of GBV-C RNA (12%–24%) and anti-E2 (14%–40%) in HIV-negative random populations reported elsewhere in Africa [13–18]. The prevalence of GBV-C RNA among HIV-negative persons in Africa is 3–4 times higher than that reported for HIV-negative persons in developed countries [12]. With the exception of the study by Chakraborty et al. [19], to date, no study in Africa has documented the prevalence of GBV-C coinfection in HIV-infected mothers and their infants, explored the possible “anti-HIV” effects, if any, associated with GBV-C coinfection in adults and infants, and addressed the impact of GBV-C on MTCT of HIV by coinfected mothers. To our knowledge, we are the first to report the dynamics of GBV-C coinfection in a cohort of HIV-infected African mothers and their infants.

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Patients and Methods

Serum samples were obtained from a convenience sample of 75 HIV-positive African mothers and their infants who were participating in a prospective clinical investigation that examined the impact of different patterns of breast-feeding [i.e., exclusive breast-feeding, both breast-feeding and formula feeding, and exclusive formula feeding) on the transmission of HIV from mothers to their infants [20]. No women received ART. The study took place at antenatal clinics in 2 hospitals in Durban, South Africa (King Edward VIII Hospital and McCord Hospital). Women were recruited between July 1995 and April 1998. Mothers underwent follow-up evaluations when their infants were 1 week, 6 week, and 3 months of age and every 3 months thereafter. Venous blood was obtained at study entry (i.e., baseline) for measurement of differential cell count and lymphocyte subset analysis. Plasma was separated ⩽5 h after baseline and stored in aliquots at -70°C. GBV-C RNA was extracted from plasma and detected by RT-PCR, as described elsewhere [11]. RT-PCR has an estimated sensitivity of 500 genome equivalents per mL of plasma. From this cohort, we randomly selected 20 mother-infant pairs. Data on HIV-positive patients were calculated using descriptive statistics (i.e., mean values ± SDs). Among HIV-positive patients, all parameters for mothers who tested positive or negative for GBV-C RNA were compared using nonparametric Wilcoxon 2-sample tests.

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Results

GBV-C RNA was detected in 27 (36%) of 75 HIV-positive mothers. In the 20 mother-infant pairs, breast-feeding was initiated for 15 infants; 5 infants were never breast-fed (figure 1). Five of 20 mothers were viremic with GBV-C infection (figure 1). Six weeks after birth, GBV-C RNA was not detected in any of the 15 infants for whom serum samples were available; these 15 infants were born to mothers who were either GBV-C RNA positive or negative (figure 1). Of these 15 infants, 12 infants were breast-fed. Twelve weeks after birth, GBV-C RNA was detected in 3 of 18 infants for whom serum samples were available (figure 1). Two of these infants were born to mothers with GBV-C infection. One infant was breast-fed, and the other was not. The third infant who tested positive for GBV-C RNA was born to a mother who tested positive for GBV-C RNA; this infant was never breast-fed.

Figure 1
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Figure 1

GB virus type C (GBV-C) RNA status in HIV-positive mothers and their infants. The bars indicate the duration of follow-up of infants born of mothers who tested positive or negative for GBV-C RNA. Plus (+) and minus (-) signs indicate positive and negative results of GBV-C RNA testing. BF, breast-fed; M, mother; NBF, not breast-fed.

Of the 5 GBV-C viremic mothers, transmission of GBV-C to 2 infants (figure 1) was confirmed at 9 months of age by nucleotide sequencing (100% identity) [Genbank accession numbers AF398330– AF398333)] (data not shown). The GBV-C isolates recovered from mothers and infants showed a close genetic relatedness and belonged to group 5 variants from KwaZulu Natal (data not shown). One infant was breast-fed and the other was not breast-fed. Of the remaining 3 infants born to GBV-C RNA–positive mothers, GBV-C was not transmitted to their breast-feeding infants. HIV was transmitted to 3 of the 20 infants; 2 of the 3 were born to breast-feeding GBV-C RNA–positive mothers. For the remaining 3 breast-feeding GBV-C–viremic mothers, HIV was not transmitted to their respective infants.

Of the 75 HIV-positive mothers in whom GBV-C prevalence was studied, we had data on baseline differential counts and lymphocyte subsets for 55. In this group of 55, comparison of those who tested positive for GBV-C with those who did not revealed no significant difference in absolute CD4 cell counts (461.12 ± 163.28 vs. 478.42 ± 181.22 cells/µL) and CD8 cell counts (680.83 ± 320.36 vs. 862.52 ± 354.48 cells/µL) (data not shown). However, patients who tested positive for GBV-C RNA had significantly higher relative CD3 cell counts (80.0 ± 4.17% vs. 70.99 ± 19.79%; P = .015), higher γδ T cell counts (3.22 ± 1.30% vs. 2.15 ± 29.12%; P = .052), and lower CD30 cell counts (35.45 ± 17.86% vs. 50.59 ± 9.20%; P = .041), compared with those who did not (data not shown).

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Discussion

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%) [13–17] but similar to that reported for HIV-infected, immunosuppressed persons in developed countries (14%–40%) [8, 9]. 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 (figure 1). 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 1–5 days old [12].

The inability to detect GBV-C RNA 1–6 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 (figure 1). In contrast, GBV-C RNA was detected in 5% of infants (age, 5 months) born to HIV-negative African females with GBV-C viremia [16] and in 2.9% of South African neonates <4 months of age [12].

Some infants acquire GBV-C from their infected mothers, as confirmed by the sequence data (our data not shown; [16]), possibly through contact with their mothers or through breast-feeding. However, to date, GBV-C RNA has not been detected in breast milk [21], 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 [22], GBV-C replicative intermediaries have not been detected in salivary gland and gonad biopsy specimens obtained during autopsy of GBV-C RNA–positive patients [23], 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 [16, 19]. 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. [19] 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 γδ 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 [9]; that it affects cytokine expression—potentially apoptosis or HIV coreceptor down-regulation—in vivo [9]; that it alters cytokine expression and protects against THI to TH2 cytokine switching [9, 24]; and that it stimulates a strong anti-HIV cytolytic T cell response [9, 25].

Human γδ T cells possesses potent cytotoxic activity and are capable of producing a large array β-chemokines and proinflammatory cytokines that are known to interfere with HIV replication [25, 26]. In humans, γδ 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 [26, 27]. Significant alterations in the peripheral blood γδ T cell activity occur in HIV-infected individuals, which is thought to be due to “superantigens/phosphoantigents” derived from bacteria, parasites, or viruses [26]. CD30 cells are members of the TNF receptor family and, in terms of limiting viral responses, CD30 cells seem to act as “immune brakes” [28–30]. Recent studies [9], 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 [9]. GBV-C coinfection may be a marker or stimulus for the presence of other unidentified factors associated with the slower progression of HIV infection [9, 10].

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 [11, 12], the observational trends in our limited study warrants more-detailed investigations (in well-defined patient groups) of the possible “anti-HIV” effects [9] 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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acknowledgments

We thank the Medical Superintendent of King Edward VIII Hospital (Durban, South Africa) for permission to publish.

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Footnotes

  • Financial support: South African Medical Research Council, University of Natal Research Fund, and National Kidney Foundation of South Africa; and Roussell-SAGES, SAGES-Abbott, and International Journal of Experimental Pathology Research fellowships (M.A.S.).

  • Received June 9, 2003.
  • Revision received August 1, 2003.
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  1. Clin Infect Dis. (2004) 38 (3): 405-409. doi: 10.1086/381092
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