Maternal plasma viral load and neutralizing/enhancing antibodies in vertical transmission of HIV: A non-randomized prospective study
© Kamara et al; licensee BioMed Central Ltd. 2005
Received: 05 October 2004
Accepted: 24 February 2005
Published: 24 February 2005
We examined the association and interaction between maternal viral load and antibodies in vertical transmission of HIV in a non-randomized prospective study of 43 HIV-1 infected pregnant women who attended the San Juan City Hospital, Puerto Rico, and their 45 newborn infants. The women and infants received antiretroviral therapy.
A nested PCR assay of the HIV-1 envelope V3 region and infant PBMC culture were performed to determine HIV status of the infants. Maternal and infant plasma were tested for HIV neutralization or enhancement in monocyte-derived macrophages.
Twelve (26.7%) infants were positive by the HIV V3 PCR assay and 3 of the 12 were also positive by culture. There was a trend of agreement between high maternal viral load and HIV transmission by multivariate analysis (OR = 2.5, CI = 0.92, p = 0.0681). Both maternal and infant plasma significantly (p = 0.001 for both) reduced HIV replication at 10-1 dilution compared with HIV negative plasma. Infant plasma neutralized HIV (p = 0.001) at 10-2 dilution but maternal plasma lost neutralizing effect at this dilution. At 10-3 dilution both maternal and infant plasma increased virus replication above that obtained with HIV negative plasma but only the increase by maternal plasma was statistically significant (p = 0.005). There were good agreements in enhancing activity in plasma between mother-infant pairs, but there was no significant association between HIV enhancement by maternal plasma and vertical transmission.
Although not statistically significant, the trend of association between maternal viral load and maternal-infant transmission of HIV supports the finding that viral load is a predictor of maternal-infant transmission. Both maternal and infant plasma neutralized HIV at low dilution and enhanced virus replication at high dilution. The antiretroviral treatments that the women received and the small sample size may have contributed to the lack of association between HIV enhancement by maternal plasma and vertical transmission.
The rate of HIV-1 infection has been increasing rapidly among women of childbearing age. At the end of 2003 women accounted for 50% of adults living with HIV/AIDS worldwide . Consequently, the number of pediatric AIDS cases due primarily to perinatal (peripartum or intrapartum) transmission is rapidly increasing. Mother-to-child transmission accounts for more than 90% of all HIV infections in infants and children worldwide. In 2003 an estimated 2.1 million children under 15 years were living with HIV/AIDS . Zidovudine (ZDV) given as either an intensive or short course regimen significantly reduces perinatal transmission [2, 3]. However, because of its cost, ZDV is not always available in poorer countries of the world. Successful use of nevirapine therapy in preventing perinatal transmission offers hope for more affordable treatment for poor women worldwide [4, 5]. However, in 2003, only one in ten pregnant women was offered services for preventing mother-to-child HIV transmission . Further, whether treated with ZDV or nevirapine, a portion of HIV-positive women still transmit virus to their offspring vertically and the problem of maternal-infant transmission through breast milk remains unsolved. Therefore, there is need for continued studies of viral and immunological factors associated with maternal-infant transmission of HIV so that other effective and affordable strategies to prevent transmission may be developed.
Although some studies show no association between the presence of HIV neutralizing antibodies in maternal sera and the risk of perinatal transmission [6, 7], other studies report a reduction in the risk of vertical transmission in pregnant women whose sera contain neutralizing antibodies to HIV . A number of studies have indicated lower transmission rates from infected pregnant women with high antibody titer or with high affinity/avidity antibody to conserved portion of HIV-1 glycoprotein 41 , to the CD4 binding site  or the V3 loop of glycoprotein 120 [11, 12], and to the p24 Gag protein . Other studies have reported that non-transmitting mothers more frequently have such antibodies to their own virus than do transmitting mothers and that transmitting mothers rarely have neutralizing antibody against their own children's isolates [14, 15]. In contrast, a study by St. Louis, et al.  found no evidence that anti-V3 loop antibody protected against perinatal transmission. Further, a study by Lallemant, et al.  showed that mothers with higher antibody titers to peptides corresponding to the V3 region of gp120 and the immunodominant domain of gp41 had a higher risk of perinatal transmission. The authors hypothesized that women who display the broadest antibody response to V3 may be experiencing the greatest viral turnover  which could make them more at risk for transmitting virus to their offspring.
In contrast to neutralizing antibodies, non-neutralizing antibodies may enhance HIV infection by binding to the virus and facilitating its uptake by cell types that carry immunoglobulin (Fc) or complement receptors. Antibodies that enhance HIV replication in vitro by either Fc gamma receptor- or complement receptor-mediated endocytosis (FcγR-ADE or C'-ADE) have been identified in sera from HIV-1-infected individuals [19–25] and from many gp120-vaccinated volunteers [19, 20]. An in vitro study of antibody dependent enhancement (ADE) of HIV-1 infection in human term syncytiotrophoblast cell cultures suggested that both FcγR-ADE and C'-ADE may contribute to maternal-infant transmission of HIV-1 . Pancino, et al. , reported that mother-infant transmission of HIV was associated with maternal antibodies to the envelope gp160 and to a highly conserved domain of the trans-membrane glycoprotein. Mann, et al. , observed that certain combinations of antibody subclasses occurred more frequently in mothers who transmitted HIV-1 to their offspring than in non-transmitters and suggested that ADE may occur in mother-infant transmission of HIV-1. However, C'-ADE was not found to be associated with maternal-infant transmission of HIV  and the role of FcγR-ADE in maternal-infant transmission has not been determined.
Maternal plasma virus load has been shown to be strongly associated with perinatal transmission of HIV [27, 30, 31] and it was reported that there is no absolute threshold of maternal viral load below which HIV transmission does not occur . Although transmission did not occur at a threshold below 2,000 copies/ml [18, 33] or below 1000 copies/ml , more recent meta-analysis has demonstrated that occasional transmission does occur below a viral load threshold of 1,000 copies/ml . Another study indicated that viral load correlated with vertical transmission in women at the clinical stage A1 (asymptomatic) of infection .
However, the association of both viral load and enhancing activity (presumably by FcγR-ADE) in maternal plasma and vertical transmission of HIV has not formerly been examined. Thus, we examined the association of these factors (independently and combined) in vertical transmission using samples from mother-infant pairs from San Juan, Puerto Rico, previously described by Melendez-Guerrero et al . Neutralization/enhancement of a R5 tropic strain of HIV-1 subtype B by maternal plasma was examined in monocyte-derived macrophage cultures.
Results and Discussion
Number and percent of HIV positive pregnant women and infants assigned to the different AIDS Clinical Trails Group (ACTG) protocols or to zidovudine (ZDV)
ACTG Protocol #
Number of women (%)
Dose and frequency
Mother: ZDV according to 076 protocol  plus anti-HIV immune serum globulin (HIVIg) or immune globulin (Ig) (200 mg/kg) every 28 days followed by 1.0 mg/kg/hr continuous infusion during labor and delivery.
Infant: HIVIg (200 mg/kg) or normal Ig within 12 hrs of birth plus oral ZDV syrup (2.0 mg/kg) every 6 hours after birth (beginning within 8–12 h) and continuing for 6 weeks.
Mother: Didanosine (ddi) IV (1.6 mg/kg) on day one, during pregnancy, followed by an oral dose (200 mg) one week after the initial dose. Oral ddi is then administered every 12 hrs until labor starts and every 12 hrs after delivery until 6 weeks post-partum. During labor and delivery patients receive a loading dose followed by continuous infusion.
Infant: Oral ZDV syrup (2.0 mg/kg) every 6 hours after birth and continuing to week 6.
Mother: ZDV plus Nevirapine (200 mg/kg) single dose during labor.
Infant: Oral ZDV syrup (2.0 mg/kg) every 6 hours after birth and continuing to week 6 plus single dose of Nevirapine (2 mg/kg) after birth.
Mother: ZDV as in protocol 185.
Infant: Oral ZDV syrup (2.0 mg/kg) every 6 hours after birth and continuing to week 6.
Mother: Nevirapine (200 mg oral dose) or the corresponding placebo during delivery plus ZDV (as in 076).
Infant: ZDV perinatal prophylaxis (2.0 mg/kg) plus single 2.0 mg/kg oral dose of Nevirapine or Nevirapine placebo administered between 48 and 72 hrs of life.
Mother: ZDV before and after delivery as is usual but oral administration of ZDV (300 mg) every 3 hrs, 3 doses total during delivery.
Infant: Oral ZDV syrup (2.0 mg/kg) every 6 hours after birth and continuing to week 6.
Mother: Stravudine (d4T, 30–40 mg) during pregnancy and 0.05 mg/kg/hr during delivery in combination with 3TC 150 mg followed by 150 mg during delivery.
Infant: Stravudine (d4T, 1 mg/kg) single dose on day 35–42, in combination with 3TC (2.0 mg/kg/dose).
Mother: ZDV (2.0 mg/kg) every 28 days followed by 1.0 mg/kg/hr continuous infusion during labor.
Infant: Oral ZDV syrup (2.0 mg/kg) every 6 hours after birth and continuing to week 6.
Demographic and clinical characteristics of the mothers and vertical transmission
Age, source of infection, clinical status and transmission outcome for HIV-positive mothers
Age of mothers (years)a
Source of infection
IV drug use
Clinical status (CDC classification 45)
Viral load (copies/ml)b
<10,000 (range 83–9,078)
≥ 10,000 (range 10,220–484,703)
Mode of delivery
V3 PCR+ Infants
V3 PCR- Infants
Twelve (26.7%) of 45 infants were HIV V3 positive indicating that HIV transmission had occurred (Table 2). However, only three of these twelve infants were also HIV culture positive. This infection rate of approximately 7.0% observed is similar to the rate of 8.3% observed for ZDV treated mothers and infants in the 076 study . Based on the V3 PCR results an equal number of mothers with low and high viral load (6 in each group) transmitted HIV to their infants. The mean log viral load of transmitting mothers 3.77 + 0.31 (median = 3.77) was higher than of the non-transmitting mothers 3.54 + 0.15 (median = 3.44) but the difference was not statistically significant (p = 0.474). This is probably due to the small sample size. The mothers of the three infants who were HIV culture positive all had high viral load levels (484,703, 11,642 and 10,220 RNA copies/ml) but the levels in two of the three were close to the 10,000 RNA copies/ml cut-off value used to distinguish LVL from HVL. Since perinatal transmission occurs mostly at or during delivery, the viral load in the genital tract (which may be similar to maternal plasma level)  may be an important determinant in maternal-infant transmission.
The mothers of HIV V3 positive infants had a non-significantly higher mean CD4+ T count (526 cells/mm3, median = 508 cells/mm3) compared to non-transmitting mothers (mean CD4+ T count of 413 cells/mm3; median = 336 cells/mm3). Maternal CD4 cell counts have been shown to be a less effective predictor of transmission of HIV than viral load . Further, most of the women in the study (86%) had CD4+T cell counts above the 200 cells/mm3 level which is used to define AIDS. Only one of the three women whose infants were HIV culture positive had AIDS (CD4 = 149 cells/mm3). The other two women had CD4 counts of 510 and 538 cells/mm3.
Neutralization/enhancement of HIV treated with maternal and infant plasma
Neutralization/enhancement of HIV infection by plasma from 12 transmitter and 33 non-transmitter mothers and 12 HIV V3 positive and 33 HIV V3 negative infants
Plasma Dilution and effect
Transmitter mothers Number (%)
Non-transmitter mothers Number (%)
HIV V3+ infants Number (%)
HIV V3- infants Number (%)
Enhancing activity in plasma from mothers and infants
Sixty-nine percent (31/45) of plasma from mother-infant pairs were also tested in the neutralization/enhancement assay at higher dilutions (10-4 to 10-6). Examination of enhancing activity in plasma of mothers and infants showed that there were good agreements (60% or greater) in enhancement status between mother-infant pairs. For example, at 10-4 dilution, the plasma of 7 infants of 9 mothers (78%) whose plasma enhanced HIV replication also exhibited enhancement, and at 10-6 dilution, the plasma of 8 infants of 10 mothers (80%) whose plasma enhanced HIV replication also exhibited enhancement (data not shown). Comparison of p24 antigen between transmitter and non-transmitter mothers or their infants at 10-4 to 10-6 dilutions showed no significant difference between the two groups of mothers or infants. The lack of association of enhancing activity and HIV transmission in this study is similar to the findings for C'-ADE by Gras, et al. . We examined complement-independent (presumably FcγR-mediated antibody dependent) enhancement in primary human macrophages because we thought that this type of enhancement would be more relevant to HIV clinical disease and transmission. FcγR-mediated enhancement is characteristic of diseases such as dengue and feline infectious peritonitis for which ADE has been best demonstrated to occur [50, 51]. In addition, macrophages are important target cells for infection and replication in vivo by most HIV-1 variants [52–54]. However, our results showed no association between enhancing activity in maternal or infant plasma and maternal-infant transmission of HIV. The negative results could in part be due to the various anti-retroviral protocols to which the women were assigned.
Correlation between maternal and infant p24 antigen levels and maternal viral load with maternal and infant p24 antigen
Correlation (Spearman) of maternal and infant p24 antigen levels and maternal viral load with maternal and infant p24 antigen
p24 antigen (M vs I) Correlationa log (p-value)b
MVL and Mp24 Correlationc log (p-value)b
MVL and Ip24 Correlationd log (p-value)b
Maternal viral load and enhancing antibodies as predictors of vertical transmission of HIV
Univariate analysis of type of treatment, stage of HIV disease, method of delivery and CD4+ T cell count of the mothers indicated no significant association with vertical transmission of HIV (p > 0.05). The combined effect of maternal viral load and enhancing antibodies as potential risk factors for the vertical transmission of HIV-1 was examined in a multivariable model. Log viral load was treated as a continuous variable in the model and enhancement was categorized as enhancement versus neutralization. There was a trend of association between maternal viral load and transmission of HIV-1 so that the higher the viral load, the more likely mothers were to transmit HIV-1 to their infants (OR= 2.5, CI= 0.93 – 6.67, p = 0.0681). This is in agreement with other studies discussed earlier that show viral load as a predictor of maternal-infant transmission [27, 30, 31]. The non-significant result in this study is probably due to the small sample size. Also, twice as many mothers (29) in this study had low plasma HIV RNA levels (<10,000 RNA copies/ml) compared to those with high viral load levels (14 mothers). The preponderance of women with low viral load levels may be the result of the effect of the different antiretroviral protocols that the women were given during pregnancy. Whereas Dickover, et al.  showed that women given zidovudine during gestation showed an eight-fold median decrease in plasma HIV RNA levels (p < 0.001), Sperling, et al.,  have shown that ZDV treatment had only a minimal effect in decreasing maternal HIV RNA levels. In this study all of the women except one (given stravudine) received ZDV treatment and in most cases ZDV was given along with one other anti-retroviral drug or with HIVIg (Table 1). There was no significant association between enhancing activity (based on p24 antigen values) in the plasma of mothers who transmitted HIV-1 to their infants based on the HIV V3+ status of the infants (OR = 0.92, CI = 0.41 – 2.07, p = 0.8492).
In agreement with published data, multivariate analysis showed a trend of association between maternal viral load and maternal-infant transmission of HIV. The non-significant difference in the mean log viral load of transmitting and non-transmitting mothers is probably due to the small sample size. No significant associations were found between HIV antiretroviral treatment protocols, classification of HIV disease, method of infant delivery and CD4+ T cell count of the mothers and vertical transmission of HIV. Both maternal and infant plasma significantly neutralized HIV infection at low (10-1) dilution and enhanced virus replication at higher dilution (10-3). Neutralizing and enhancing antibodies can occur together in the blood of HIV positive individuals and the neutralizing effect can be lost at high plasma dilution.
There were good agreements in the neutralizing or enhancing activity of the plasma from mothers-infant pairs. That is, when plasma of the mothers neutralized or enhanced HIV infection, their infants' plasma showed similar activity. However, there was no significant association between virus enhancement by maternal plasma and vertical transmission of HIV. Thus, enhancing activity in plasma of these HIV-infected mothers was not a dominant factor in vertical transmission of HIV.
Collection, processing and testing of maternal and infant blood samples for HIV
Blood samples were taken from the mothers during each trimester of pregnancy and during delivery. Blood samples from the infants were collected from the umbilical cord at birth and at 1–2, 3–4 and 5–12 months. Blood was collected in vacutainer tubes containing ACD anticoagulant and centrifuged at 2500 rpm for 15 minutes. The plasma was stored frozen (-20°C) for use in maternal viral load and HIV neutralization/enhancement assays. The remaining blood was diluted in phosphate-buffered saline (PBS) pH 7.4 and processed by Ficoll-hypaque density gradient for cell isolation. For virus isolation, one million cells from each mother or infant were co-cultured with HIV seronegative donor cells previously stimulated by PHA as described in the ACTG virology manual . The remaining cells (105) were stored frozen at -85°C. The HIV status of the infants was determined using a nested PCR assay of the HIV-1 envelope variable (V3) region as previously described [37, 56]. This V3 PCR assay was conducted in duplicates and repeated on the infant samples at 1–2 months, 3–4 months and 5–11 months. Culture for HIV was repeated on infant samples collected at 3, 6 and 12 months and all except 3 infants were culture negative.
Determination of maternal viral load
HIV RNA copies in maternal plasma was determined by the amplicor HIV monitor test (Roche Diagnostics, Branchwater, NJ, USA) at the Puerto Rico ACTG-certified laboratory . A 142 base-pair sequence in the HIV gag gene was amplified by RT-PCR for viral load determination. The mean log viral load was calculated and compared between transmitting and non-transmitting mothers to determine the effect of maternal viral load on HIV vertical transmission.
Preparation and titration of HIV-1BaL for the neutralization/enhancement assay
HIV-1BaL stock was prepared in primary macrophages as reported previously by Jolly . Briefly, HIV-1BaL supernatant fluid (1 × 104.6 TCID50/ml) obtained from the NIH AIDS Research and Reference Reagent Program was used to inoculate fresh cultures of macrophages grown on 75 ml tissue culture flasks. The cultures were washed 24 hours later and incubated with fresh media. Supernatant fluids were harvested at 7 and 14 days post-infection, clarified by centrifugation at 1800 rpm for 10 minutes and used as stock virus for these studies. The stock contained 5 × 105 TCID50/ml.
A neutralization/enhancement assay was conducted using maternal or infant samples and HIV-1BaL. Maternal plasma samples collected during the third trimester of pregnancy were used in these assays since most prenatal HIV infections occur in the third trimester . Briefly, 10-fold dilutions of heat inactivated (56°C for 30 min) plasma samples were mixed 1:1 with 103 TCID50/ml of virus and pre-incubated at 37°C for 30 min. The mixtures were then inoculated into replicate cultures of monocyte-derived macrophages as prepared previously  in 8 well chamber slides and incubated at 37°C for 6 hours in a 5% CO2 incubator. The inocula were removed and the cells washed, and incubated with fresh media for up to 8 days. Culture supernatant fluids were then collected on days 2, 4, 6, and 8 and tested for p24 antigen using the Coulter assay (Coulter, Miami, FL, USA). Cultures treated with HIV-negative sera were used as controls. All maternal and infant plasma samples were tested at three 10-fold dilutions; 69% of samples were tested up through six 10-fold dilutions. Two independent assays were conducted for each maternal or infant plasma sample and each sample was run in duplicate on each assay (4 replicates).
Descriptive statistics such as mean, median, range were calculated to summarize maternal characteristics such as viral load, CD4+ T cell count and p24 antigen levels. The number of HIV vertical transmission among infants was summarized and the univariate association of maternal characteristics, such as, treatment (type of antiretroviral therapy), stage of disease based on the 1993 CDC classification , method of delivery (C-section vs. vaginal), and CD4+ T cell count, with HIV transmission in infants was evaluated using the Fisher's exact test. The simultaneous effect of maternal viral load and p24 levels on infant transmission was evaluated using the logistic regression model. Odds ratio and 95% confidence intervals were calculated for the effect of both factors in the model.
Correlation between maternal versus infant p24 antigen levels and between maternal viral load and maternal or infant p24 antigen levels was evaluated using the Spearman's correlation coefficient. Enhancement, decrease (neutralization), or no change in p24 levels compared to seronegative control was assessed for mother-infant pairs. The distribution of virus p24 antigen was compared between transmitting vs. non-transmitting mothers and between HIV V3+ infants and HIV V3- infants using Fisher's exact test.
This study was supported by the CFAR-RCMI supplement grant P30-AI-2767 from the NIAID/NIH, the "Research Centers in Minority Institutions" award G12RR-03051 from the National Center for Research Resources, NIH, award 3 S06 GM08224 from the National Institutes of General Medical Sciences, NIH, and awards RO1 AI 39194 and 5P30 AI27767 from the NIAID/NIH. We appreciate the contribution of the nurses who followed the mothers and infants in the study and the pediatrician in charge of the ACTG clinic. We thank Gill Nieves for help in developing viral macrocultures and M. Vega and G. Hillyer for help with phenotypic and viral load analyses, respectively. HIV-1BaL from Dr. Suzanne Gartner and Dr. Mikulas Popovic was obtained through the AIDS Research and Reference Reagent Program, Division of AIDS, NIAID, NIH.
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