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Maternal versus paternal inheritance of HLA class I alleles among HIV-infected children: consequences for clinical disease progression

Kuhn, Louise; Abrams, Elaine Ja; Palumbo, Paulb; Bulterys, Marcc; Aga, Ronnied; Louie, Lesliee; Hodge, Thomasffor the Perinatal AIDS Collaborative Transmission Study (PACTS)


Objective: When children acquire HIV infection from their mothers (with whom they share at least 50% of their HLA alleles), they acquire virus with a history of encounter with maternal HLA-mediated immune responses. We investigated whether maternal HLA selection pressures on the virus would adversely influence clinical outcomes of HIV-infected children.

Methods: We tested whether time to AIDS diagnosis or death, among a cohort of 59 HIV-infected children in New York City followed from birth for up to 12 years, was associated with maternally- or paternally-inherited child HLA class I alleles, and with HLA similarity between mother and child.

Results: HIV-infected children with an HLA allele usually associated with slow disease experienced a slower progression to AIDS or death only if the allele was paternally inherited. If the allele was present in the mother, no association was observed. Children who were homozygous or who shared both alleles with their mothers at more than one HLA class I locus were more likely to progress to AIDS or death than other children (relative hazard, 3.46; 95% confidence interval, 1.24–9.71).

Conclusion: Genetic similarity between mother and child may compromise the child's capacity to control HIV replication when the virus is acquired from the mother. HLA-mediated selective pressures on the virus in a transmitting mother–infant pair may undermine future HLA-mediated viral control in the child.

From the Gertrude H. Sergievsky Center, College of Physicians and Surgeons, and Department of Epidemiology, Mailman School of Public Health, Columbia University, aHarlem Hospital Center, and Department of Pediatrics, College of Physicians and Surgeons, Columbia University, New York, New York, the bDepartment of Pediatrics, University of Medicine and Dentistry, New Jersey Medical School, Newark, New Jersey, the cDivision of HIV/AIDS Prevention, National Center for HIV/STD/TB Prevention, Centers for Disease Control and Prevention, Atlanta, Georgia, dLaboratories at Bonfils, Denver, Colorado, the eChildren's Hospital Oakland Research Institute, Oakland, California, the fNational Center for Infectious Diseases, Centers for Disease Control & Prevention, Atlanta, Georgia, USA.

Correspondence to L. Kuhn, Gertrude Sergievsky Center, College of Physicians & Surgeons, Columbia University, 630 W 168th Street, New York, NY 10032, USA.

Received: 29 August 2003; revised: 6 November 2003; accepted: 28 January 2004.

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One of the challenges to understanding immune control of HIV infection is substantial viral polymorphism [1]. On a population level, viral heterogeneity is manifest in distinct subtypes circulating within specific geographic and epidemiologic contexts and including extensive within-subtype diversity [2]. On an individual level, an HIV-infected person harbors many genetically distinct viral variants which evolve further with time [3]. High rates of error-prone viral replication fuel this diversity which is the basis of the development of antiretroviral drug resistance [3] and which may also be a cornerstone of host immunity failure [1,2].

HIV-specific cytotoxic T-lymphocyte (CTL) responses are thought to play an important role in control of HIV replication in the absence of antiretroviral drug therapy [4]. Among HIV-infected adults, CTL responses can be detected soon after primary infection, and the strength and breadth of these responses influence the establishment of an equilibrium between viral replication and immune control (viral set-point) [4]. However, CTL responses ultimately fail among all except a small group of long-term non-progressors. Viral mutation at critical amino acids in the epitopes recognized by CTL may allow the virus to evade detection [5]. Similar to the situation of drug resistance, viral variants with mutations in crucial epitopes have survival advantage and can outcompete variants susceptible to immune control [5]. Clear evidence for the importance of CTL escape has been obtained in animal models [6,7]. In humans, selection of CTL escape mutants has also been demonstrated [8,9] but it is unclear how widespread or clinically relevant the process is.

In support of the importance of viral evasion of CTL, a large population study demonstrated that HIV heterogeneity among infected individuals was shaped by their HLA [10]. HLA-influenced viral polymorphisms were, in turn, correlated with higher viral load [10]. Since CTL responses are HLA class I restricted, viral escape mutations are HLA-specific [11]. In this same study, few escape mutants were observed to be associated with the most prevalent class I allele, HLA*A02 [10]. HLA immune pressure may have already influenced the evolution of circulating viral variants in the population to avoid detection by the most common HLA alleles [12].

Pediatric HIV infection offers a unique opportunity to investigate HLA-mediated influences on the evolution of HIV. With mother-to-child transmission, virus acquired by the child has a history of encounter with maternal HLA-mediated immune responses and is transmitted to a genetically-related individual (rare for other routes of infection). The relevance of maternal HLA selection pressure on virus transmitted to a child was demonstrated for the class I allele B*27 [13]. If this allele was inherited from the mother, the child harbored viral escape mutants which evaded the usually protective CTL response [13].

We sought to investigate whether HLA selection pressure would be evident among a broader population of vertically infected children and whether it would have clinically detectable consequences for progression to AIDS or death. We formulated two related hypotheses: first that HLA alleles usually associated with delayed disease progression would be ineffective among HIV-infected children if the alleles were inherited from the mother; and second that children with greater similarity to their mothers with respect to their HLA genes would have faster disease progression. The underlying idea is that virus transmitted to the child has evolved to evade maternal HLA-mediated responses. To the extent that the child relies on these same HLA-mediated responses to contain viral replication, the child's immune response is set up to fail.

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Study population

The study population included 62 HIV-infected children born to HIV-infected mothers between 1986 and 1995 in New York City and enrolled in the Perinatal AIDS Collaborative Transmission Study (PACTS). PACTS is a multi-site, natural history study that recruited HIV-infected women during pregnancy or shortly after delivery and followed the women and their children prospectively with regularly scheduled tests to determine transmission. Children were considered to be HIV infected if they had two or more positive HIV DNA PCR tests at any age, had an AIDS-defining illness, or if they died with an HIV-related condition. HIV-infected children were examined at regular intervals from birth up to more than 12 years of age to assess clinical progression. The cohort is described in more detail elsewhere [14–16]. A random sample of HIV-infected children from the cohort was selected from those with both a maternal cell sample and at least two infant cell samples stored in the repository. Three children had to be excluded because child or mother available cell samples were insufficient for typing. Thus the analysis is based on 59 children.

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HLA genotyping

HLA class I genotyping (HLA-A, -B, -C) of mothers and children was undertaken. HLA A and B Sequence Specific Oligonucleotide Probe molecular typing was performed using Orchid Diagnostics HLA A and B NMDP kits (Orchid Diagnostics, Stamford, Connecticut, USA). The HLA Cw reverse SSOP molecular typing was performed using Dynal AUTORELI kits (Dynal Biotech Inc, Lafayette Hill, Pennsylvania, USA). HLA-A, B & Cw gene products were amplified by PCR using locus-specific primers. For HLA A and B typing, a sample of the amplified product was dotted on a 384-dot blot nylon membrane and then probed with locus-specific probe sets that were labeled with alkaline phosphatase. Hybridization of specific probes was imaged using CDP Star substrate and X-ray film. The results were scanned and analyzed with Orchid QuickType Analysis software. The HLA-Cw typing assay used the reverse line blot principle with probes bound as successive horizontal lines on membrane strips. The biotinylated Cw primers tagged the DNA during amplification with biotin, which was detected with streptavidin/horseradish peroxidase and the chromagen, tetramethylbenzidine. The assay was run on the AUTORELI and the results were analyzed with Dynal's Pattern Matching Program software.

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A child's HLA allele was considered to be consistent with a maternal origin if the same allele was also detected in the mother, and was considered to be consistent with a paternal origin if it was not. Since the father's HLA type was not ascertained, maternal inheritance could not be definitively inferred when mother and child shared two alleles. For the purposes of this analysis in these ambiguous situations, the alleles were included in the group defined as consistent with a maternal origin (since the allele was present in the mother even if the child had not necessarily inherited it from the mother). To investigate possible bias of this definition, analyses were repeated in the subgroup for which inheritance could be accurately inferred.

Alleles consistent with a maternal or paternal inheritance (as defined above) were grouped into three categories: (i) those associated with slow, or (ii) rapid disease progression, and (iii) those with no prior consistent associations with disease progression. Categorization was derived from a multi-cohort study of over 800 HIV-infected adults in the USA with a known date of seroconversion who were followed for 5–10 years to determine clinical disease progression to AIDS or death [17–19]. Slow disease alleles were defined as those with longer time to AIDS or death: either a statistically significant (P < 0.05) increase, or a relative hazard less than 0.5. These alleles were: A*11, B*27, B*51, B*57, B*58, Cw*2, Cw*14 [19]. Rapid disease alleles were defined as those with a statistically significant (P < 0.05) shorter time to AIDS or death. These alleles were: B*35, B*53, Cw*4 [19]. All other alleles were considered to have no consistent association with disease progression. This study was chosen for the classification schema because of its methodological strengths, including large numbers from several distinct cohorts, high-resolution HLA typing, selection of seroincident cases, and long follow-up to clinically meaningful endpoints.

Mothers and children always share at least one allele at each gene. Children with paternally inherited HLA alleles that do not differ from their mothers’ non-transmitted alleles are immunologically more similar to their mothers, thus their HLA alleles may be less likely to resist disease progression. Therefore, the number of potentially ineffective mother–child HLA combinations was counted. These included pairs where the two inherited alleles were identical to the two maternal alleles, or where the child was homozygous. In both of these cases, the child's HLA alleles are both already present in the mother. If neither allele at a specific locus was shared between mother and child (presumably typing error: 3/59 HLA-A, 1/59 HLA-B, 0/59 HLA-C) mother and child were classified as dissimilar at that locus.

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Statistical analyses

Time to developing an AIDS-defining condition or death by genotype was analyzed using Kaplan–Meier life-table methods and tested using two-tailed log-rank tests. Multivariate analysis was performed using Cox Proportional Hazards models. The proportional hazards assumption was tested for each model. Kruskall–Wallis tests were used to compare log-transformed HIV RNA copy numbers between groups.

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Study population

Included in the HLA analysis were 59 HIV-infected children born in New York City between 1986 and 1995 and followed from birth for up to 12 years. Among these HIV-infected children, 36% had progressed to AIDS or had died before 24 months of age, and 22% had died before 24 months of age. These rates of progression were similar to comparable members of the overall cohort. Children included in the HLA analysis were more likely to be female and less likely to have been born preterm than the overall cohort, but other characteristics were similar (Table 1).

Table 1

Table 1

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Maternal versus paternal inheritance of HLA class I alleles and disease progression

Associations between HIV-infected children's HLA alleles and clinical disease progression differed depending on whether the allele was consistent with inheritance from the mother or from the father (Table 2, Fig. 1). By 24 months of age, 14% of HIV-infected children who inherited one or more of the slow disease progression alleles from their father had progressed to clinical AIDS or died, compared to 48% of children who did not inherit a slow disease allele solely from their father (P = 0.049). Considering mortality alone, 5% of HIV-infected children who inherited a slow disease allele from their father had died by 24 months of age, compared to 32% of children who had not (P = 0.022). Children who inherited these same slow disease alleles from their mothers had no apparent clinical benefits (Table 2). Among the subgroup of children sharing only one allele with their mothers at all three loci (and thus for whom the maternal- or paternal-inheritance attribution was unambiguous), the association between slower progression and paternally-inherited slow disease alleles remained significant (P = 0.036).

Fig .1.

Fig .1.

Table 2

Table 2

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.

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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).

Table 3

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.

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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).

Fig. 2.

Fig. 2.

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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.

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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 [22]. 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 [13].

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 [23]. 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) [24]. 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 [28]. 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 [9]. 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 [29] is unclear. Possibly, rapid disease alleles are not intrinsically risky, but rather signify the absence of other protective alleles [30]. 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 [33], although deficiencies of HIV-specific CTL responses do not appear to extend to children who acquired HIV through receipt of blood products [34].

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 HLAHIV associations differ between populations. For example in a large Zambian study, strong HLAHIV disease progression associations were observed, but the specific alleles of relevance were markedly different from those observed in studies in the USA [41].

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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    HIV; mother to child transmission; HLA; maternal; paternal; inheritance

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