Children who inherited one or more of the alleles associated with rapid disease progression from their fathers progressed more rapidly to AIDS or death (P = 0.012). Children who inherited one or more of these rapid disease alleles from their mothers had no significant clinical disadvantage (Table 2). The association between faster progression and paternally inherited rapid disease alleles remained in the same direction but dropped below significance (P = 0.059) among the smaller subgroup sharing only one allele with their mothers at all loci.
We repeated the above analyses considering only B*27 and B*57 as slow disease alleles and B*35 and B*53 as rapid disease alleles. Time to AIDS or death among those with paternally inherited B*27 or B*57 was in a direction consistent with a longer time but did not reach statistical significance [relative hazard (RH), 0.89; 95% confidence interval (CI), 0.27–2.99]. Time to AIDS or death was significantly shorter among those with paternally inherited B*35 or B*53 (RH, 2.58; 95% CI, 1.03–6.44). For time to death RH was 0.47 (95% CI, 0.62–3.58) and 3.30 (95% CI, 1.14–9.54) for the revised slow and rapid allele categories, respectively. Maternal inheritance of these alleles showed no association with disease progression.
Ineffective mother–child HLA combinations
HIV-infected children with two class I loci defined as potentially ineffective (i.e., homozygous or identical to their mother) were three times more likely to progress to AIDS or death (RH, 3.46; 95% CI, 1.24–9.71). Having only one of three loci defined as ineffective did not appear to influence disease progression (Table 3).
Considering homozygosity alone, 10 (17%) children were homozygous at one or more loci, but their disease progression did not differ significantly from others (Table 3). Only one child was homozygous at more than one locus, and was a rapid progressor who developed AIDS by 9 months of age and who died aged 16 months. Considering mother–child identity alone, 19 (32%) children were identical to their mothers at one or more locus, but their disease progression did not differ significantly from others (Table 3). Three children were identical to their mothers at more than one locus. Two of these developed AIDS before 9 months of age and subsequently died during follow-up.
Maternal HIV disease markers, race, and antiretroviral drug use
Markers of more advanced maternal disease did not explain associations between HLA categories and disease progression. After adjustment simultaneously for low maternal CD4 cell count (< 200 × 106 cells/l) and maternal AIDS diagnosis before delivery, paternally inherited slow disease alleles (RH, 0.40; 95% CI, 0.16–1.01), rapid disease alleles (RH, 2.67; 95% CI, 1.04–6.88) and two ineffective loci (RH, 3.46; 95% CI, 1.24–9.71) continued to be associated with disease progression. With further adjustment for maternal viral load (available for 38 pairs), the above associations remained consistent (RH, 0.26; 95% CI, 0.07–0.91; RH, 2.40; 95% CI, 0.80–7.21; RH, 4.44; 95% CI, 1.22–16.22, respectively).
Among 36 children of African–American mothers (the largest racial subgroup), parental origin and allele sharing associations were similar. Associations were also similar stratifying by child's sex, preterm delivery, low birth weight, maternal antiretroviral drug use during pregnancy, maternal AIDS diagnosis or CD4 cell count (data not shown). There was no evidence of effect modification by CD4 cell count or maternal AIDS but power is limited to detect interactions.
Since the cohort was born between 1986 and 1995, few HIV-infected children were treated with effective combination antiretroviral drug therapy during the first years of life, although dual- and mono-therapy were more common and triple combinations started to be used around 1998. To consider possible consequences of drug treatment, analyses were repeated censoring follow-up observations when any antiretroviral drug was started. Associations between HLA categories and disease progression were slightly stronger when any benefits of antiretroviral drug treatment were essentially censored out (Fig. 2).
Child viral load over the first year of life
We also examined the dynamics of viral load changes over the first year of life. We divided the first year into the period of primary viremia (0–60 days) and the period of viral containment (61–365 days). The peak plasma viral load attained between birth and 60 days did not differ by the HLA profile. The mean (standard deviation) peak viral load was 5.72 (1.07) HIV RNA copies/ml in the group who inherited a slow disease allele from their father (slow disease HLA profile), 5.87 (1.08) HIV RNA copies/ml in the group who inherited a rapid disease allele from their father or who had two ineffective loci (rapid disease HLA profile) and 5.56 (0.91) HIV RNA copies/ml in all others. Over the subsequent period where viral load was expected to decline (61–365 days), the mean viral load measured at the oldest available age was significantly higher among those with a rapid disease HLA profile [6.34 (0.47) HIV RNA copies/ml] compared to those with a slow disease HLA profile [5.34 (0.48) HIV RNA copies/ml] (P = 0.003) or to all others [5.76 (0.92) HIV RNA copies/ml] (P = 0.017). There were no statistically significant differences in the use of antiretroviral drugs by the HLA profile.
HIV infection among children generally has a worse prognosis than among adults. In the absence of effective therapy, about a quarter of HIV-infected children progress to AIDS and 10–15% die within the first year of life [20,21]. Interestingly, children who acquired HIV through blood transfusions, even during the neonatal period, tend to have a better prognosis . Mother–child genetic similarity may play a role in explaining these differences in the natural history of HIV infection between children and adults, and those children who have greater than average similarity with their mothers may fare worst.
Processes described for HLA*B27 may underlie these observations. A detailed study of four HIV-infected mother–child pairs observed mutations in viral epitopes and defective CTL responses among three children sharing the usually protective B*27 allele with their mother. In contrast, the one child who inherited B*27 from the father had robust CTL responses and was a long-term non-progressor .
Our findings suggest that these processes described for B*27 may be more common, extending to other protective HLA class I alleles, and may have clinically detectable consequences for disease progression among HIV-infected children in general. This result may be surprising since it has proved difficult to demonstrate associations between CTL escape and maternal–infant HIV transmission [23,24]. In one report, although amino acid substitutions within targeted CTL epitopes were more frequently detected among transmitting compared to non-transmitting mothers, the most prevalent epitope sequences among infected children were CTL susceptible . No clear link between escape from a dominant HLA-A*02-restricted CTL epitope and transmission was observed in another study. The authors hypothesized this to be due to lack of immunologic relevance of this epitope (not a conserved viral region, inconsistent associations between different escape variants and peptide binding, and lack of association with viral suppression) . Escape may, paradoxically, help identify those HLA alleles most strongly associated with more effective CTL responses.
We grouped HLA alleles as being associated with either slow or rapid disease progression based on data from a large, multi-cohort adult study [17–19]. A limitation of our grouping is that not all of the individual alleles have been independently replicated in other studies [25–27]. HLA-disease associations are often difficult to replicate, in part due to substantial HLA polymorphism and variation across populations, further complicated, in the case of HIV, by extreme viral polymorphism . Thus failure to find an association with maternally inherited alleles may simply suggest poor applicability of the classification schema to this study population. Arguing against this interpretation, however, are the significant associations observed with HLA categories based on paternal inheritance, providing some internal validity. Two of the protective alleles (B*27 and B*57) included in our grouping are well established, and beneficial immunodominant CTL epitopes have been identified . Our study, however, has insufficient power to test the hypothesis for specific alleles individually.
Clinical benefits of maternally inherited slow disease alleles may be abrogated by CTL escape, but why maternal inheritance should attenuate risks of rapid disease alleles  is unclear. Possibly, rapid disease alleles are not intrinsically risky, but rather signify the absence of other protective alleles . If so, our observations may suggest an attenuation of protective benefits of non-risk alleles, rendering all alleles shared with the mother uninformative to predict disease progression.
Acute infection among children is characterized by exceedingly high viral levels during the first months of life which begin declining thereafter. Viral levels remain higher than in adults, consistent with more rapid disease progression [31,32]. We observed little ability to reduce viremia over the first year of life among those with an ineffective HLA profile suggesting that the closely matched immunologic environment of the child may fail to control maternally transmitted virus. HIV-specific CTL responses in young HIV-infected infants tend to be weak , although deficiencies of HIV-specific CTL responses do not appear to extend to children who acquired HIV through receipt of blood products .
Maternal–infant HLA concordance has been associated with an increased risk of perinatal HIV transmission [35,36]. This raises concern about confounding by advanced maternal disease which is associated with transmission and with more rapid disease progression in the infected child [15,37–39]. However, we did not observe that low CD4 cell count, HIV-related clinical symptoms in the mother, or high maternal viral load, attenuated the genetic associations when included in multivariate models.
Maternal–infant HIV transmission offers a window to observe viral evasion of HLA-mediated immune control and may alert us to possible consequences that may only be evident in the adult population after decades. HLA alleles currently associated with better prognosis may be less relevant in the future. HLA selection pressure may also help explain why HLA–HIV associations differ between populations. For example in a large Zambian study, strong HLA–HIV disease progression associations were observed, but the specific alleles of relevance were markedly different from those observed in studies in the USA .
These findings support the hypothesis that vertically infected children with immune environments more similar to their mothers’ are more likely to progress rapidly. The cohort was recruited prior to use of effective antiretroviral drugs allowing HLA-mediated pressure to be observed directly and consequences for clinical disease progression over many years of follow-up to be quantified. HLA-mediated selective pressures on the virus in a transmitting mother–infant pair may undermine future HLA-mediated viral control in the child.
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Keywords:© 2004 Lippincott Williams & Wilkins, Inc.
HIV; mother to child transmission; HLA; maternal; paternal; inheritance