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Increasing data support host genetic factors as important determinants of human immunodeficiency virus type 1 (HIV-1) susceptibility, mother-to-child transmission (MTCT) and disease progression. Of these genetic mediators, those impacting innate and adaptive immune responses appear to play a critical role in viral infectivity and pathogenesis. During primary infection, CCR5 using virus is predominantly transmitted and polymorphisms that affect the expression of CCR5 alter the risk for MTCT and rate of disease. Chemokines that naturally bind to co-receptors alter infectivity and viral pathogenesis. Additional genes that affect innate immunity including those encoding for MBL2 and those modulating the adaptive immune response including CX3CR1 and HLA types can significantly modify susceptibility and response to HIV-1 infection. As young children develop, the dependence on certain arms of the immune system varies and can alter the effect of genetic variants. Additionally, host genetic factors may alter the response to antiretrovirals. Finally, because HIV-infected children progress more rapidly than adults and have fewer background co-factors such as drug use and co-infections, the effects of host factors on HIV-1 disease may be more clearly identified. In this review, we summarize available data on the impact of host genetics on MTCT and disease progression of HIV-infected children.
Remarkable progress has been made in the interruption of human immunodeficiency type-1 (HIV-1) mother-to-child transmission (MTCT) and treatment for HIV-infected children. However, despite these advances many challenges remain to eliminate MTCT through the safest ways possible and in optimizing antiretroviral therapy for pregnant women and children in developed and developing countries. Infants and children can be particularly susceptible to the long-term effects of antiretroviral exposure. Therefore, approaches that lead to optimal drug exposure with the least potential for toxicity for the individual patient are critical if HIV-infected and exposed children are to lead healthy and productive lives. Moreover, the recent HIV-1 vaccine failures dramatically demonstrate the need to further understand the interactions between host and virus.
HIV usually uses CD4 and a coreceptor to infect cells. The most common HIV coreceptors are the chemokine receptors CCR5 and CXCR4. While most primary infections involve viruses that use CCR5 as a coreceptor, CXCR4 using virus is often identified in persons with more advanced disease and is associated with more rapid disease progression. To enter target cells. HIV interacts with the CD4 receptor via its gp120 protein, thereby stimulating a conformational change in gp120, which exposes a portion of transmembrane glycoprotein gp41, and allows access of the gp120 V-loop to either CCR5 or CXCR4. Subsequently, a peptide in gp41 causes the fusion of the viral envelope and host cell membrane, and allows the viral capsid to enter the target cell.
Host factors are important determinants of susceptibility and pathogenesis of infectious diseases in children and adults. Identifying genetic variants that influence the response to HIV-1 can provide insights into approaches to predict disease progression, can lead to development of new treatments, and can provide new immunologic targets for vaccine development. In this review, we summarize the available data on the impact of host genetics on MTCT and treatment of HIV-infected children. Where appropriate the differences between findings in children compared to adults are discussed. Additionally, we describe the role a particular variant may play in the control of HIV-1 through innate versus adaptive immunity.
Host and microbial genetics are important determinants of infection and disease outcome. Viruses subvert the immune system by mimicking cellular genes to gain entry into cells and to avoid immunologic detection. With the identification that HIV-1 uses chemokine receptors for cell binding and entry, variants in genes encoding these receptors and their natural ligands have been shown to modify the risk for infection and disease progression. Several single nucleotide polymorphisms (SNPs) within the CC chemokine receptor 5 (CCR5) coding and regulatory region appear to affect HIV-1 disease. For HIV-1 infection of adults and children, CCR5 is a critical co-receptor modulating perinatal transmission (1–3) with a deletion of 32-bp from the coding region of the CCR5 gene (Δ32) providing almost complete protection against HIV-1 infection in individuals with the homozygous mutant genotype (CCR5-Δ32/Δ32) (4–7). Individuals heterozygous for CCR5-wt/Δ32 are less likely to be infected with HIV-1 and show a slower rate of disease progression (2, 3, 5, 6, 8, 9). Several SNPs in the regulatory region of the CCR5 gene, including a G to A polymorphism at position 59029, a T to C polymorphism at position 59353 and a C to T polymorphism at position 59356 have been reported to alter the rate of disease progression to AIDS (8, 10).
A polymorphism in the coding region of the CC chemokine receptor 2 (CCR2), a minor HIV-1 co-receptor, at position 180 (G to A polymorphism) leads to expression of an isoleucine replacing a valine at amino acid position 64 (designated as CCR2-64I) and has been associated with slower disease progression of HIV-1 infected adults (9, 11). Similarly, in the 3’-untranslated region of the gene encoding the CXC chemokine SDF-1α, the only natural ligand of the HIV-1 co-receptor CXCR4, a G to A polymorphism at position 801 has been reported to delay the rate of disease progression to AIDS in its homozygous (A/A) form in an initial report (12), but not by others (13–15). The SDF1-3’-A polymorphism has also been reported to be associated with increased perinatal transmission of HIV-1 (16). Some of the studies demonstrating these effects are discussed below and are summarized in Table 1 and Figure 1 and Figure 2.
In a cohort of over 1000 HIV-infected children who participated in Pediatric AIDS Clinical Trials Group (PACTG) 152 or 300 protocols and received mono- or dual-nucleoside reverse transcriptase inhibitor (NRTIs) treatment before the availability of effective antiretroviral therapy, we studied the effects of CCR2-V64I, CCR5-wt/Δ32, CCR5-59029-G/A, CCR5-59353-T/C, CCR5-59356-C/T and SDF1-3’-G/A polymorphisms on the rate of disease progression and neurological impairment (17). These studies confirmed that the CCR5-wt/Δ32 genotype is associated with slower disease progression. HIV-infected children with the CCR5-wt/Δ32 genotype at study entry had higher mean CD4+ lymphocyte counts, CD4+ percentages and cognitive scores, and lower plasma HIV-1 RNA levels than those with the wt/wt genotype. Moreover, children with the CCR5-wt/Δ32 genotype were less likely to be severely impaired (cognitive index score <70) at baseline or experience CNS impairment than those with the homozygous wild-type. Although there was a clear benefit observed from the CCR5-wt/Δ32 genotype, protection was incomplete and some children did experience disease progression in this group. Because HIV-1 co-receptor usage may change over time in a given individual, it is possible that a switch from CCR5 to CXCR4 usage, which is associated with accelerated disease progression in adults and children (18–21), may have occurred in some of those who progressed.
Despite the important impact of the CCR5-32bp deletion in delaying disease (12% versus 26% of those with and without the 32bp deletion progressed within two years), the Δ32 variant occurred in only 6% of the total cohort. In contrast, a genetic variant within the CCR5 promoter region, 59029-A/A was found in ~25% of HIV-infected children and was associated with an almost 50% increase in disease progression when compared to those with the G/A or G/G genotype. Therefore, on a population basis, the CCR5-59029-G/A genetic variants have a greater overall impact on HIV-related disease in children than the CCR5-wt/Δ32 variant. Another variant in the CCR5 promoter region at position 59353-C/T was found to have an almost 40% greater risk for children with the C/C genotype having a cognitive-index score of <70 compared to those with the T allele.
The impact of CCR2 on HIV-related disease remains controversial. Although CCR2 is recognized as a minor co-receptor for HIV-1 in vitro, whether it serves as a co-receptor in humans remains to be clarified. However, several studies in adults have identified that a CCR2 variant, CCR2-64I, alters disease progression (9, 11, 13). In contrast, we have found no association between disease progression and death with any of the CCR2 genotypes. The reason(s) for the different effects observed in children versus adults with the CCR2 variants are unclear. However, it is likely that the alteration in disease progression found in adults results from modulation of the immune response to HIV-1 as related to the binding of CCR2 with its ligand MCP1 (CCL2). It is possible that the broad immaturity of the immune system of young children compared to adults masks any effect this interaction may have on viral control.
The natural ligand for CXCR4, SDF-1, has also been associated with HIV-1 disease in some studies of adults and children. In our own research, children with the CCR5-wt/wt genotype and the SDF1-3’-A/A variant were more likely to experience disease progression than those with either the G/A or G/G genotypes. These findings are consistent with other studies in children that reported slower disease progression associated with the SDF1-3’-A/A genotype (22, 23). However, only a small number of individuals within a given population have the SDF1-3’-A/A genotype (<2% in our studies).
Clinical monitoring of infected persons relies on monitoring of CD4+ lymphocyte count and viral load where the plasma HIV-1 RNA predicts that rate of disease progression, while the CD4+ count is used as a predictor of the current risk an individual will develop an HIV-related complication. Our studies of the chemokine receptor CX3CR1 demonstrate how host genetics has the potential to provide additional information about an individual’s risk for disease progression and related complications independent of CD4+ count and viral load (24).
CX3CR1 belongs to a family of G-protein coupled receptors and is a leukocyte chemotactic and adhesion receptor for fractalkine (25) and may also serve as a minor HIV-1 co-receptor (26, 27). Two non-synonymous polymorphisms in the coding region of the CX3CR1 gene were initially identified as possibly being associated with more rapid disease progression in HIV-1 infected adults (28): a ‘G’ to ‘A’ polymorphism at nucleotide position 745 changes a valine to isoleucine at amino acid position 249 (V/I249) in the sixth transmembrane domain and a ‘C’ to ‘T’ polymorphism at nucleotide position 849 changes a threonine to methionine at amino acid 280 (T/M280) in the seventh transmembrane domain of CX3CR1 protein. Faure and colleagues reported that HIV-1 infected persons homozygous for CX3CR1-M280 progress to AIDS more rapidly than those with other genotypes (29). In another study, Brumme et al found a trend toward an association of the I249-T280 and I249-M280 haplotypes with early immunological failure in HIV-1 infected adults (30).
The expression of CX3CR1 and its ligand, fractalkine, are increased during HIV-1 infection and are reduced on treatment with effective active antiretroviral therapy suggesting that they are important in directing the immune response against HIV-1 (31). Fractalkine expression has been reported to be up-regulated in the brains of AIDS patients and may be important in HIV-1 associated dementia by regulating the trafficking of monocytes in brain parenchyma (32–34). In addition, fractalkine and CX3CR1 are expressed in human neurons and glial cells (35). Our findings in HIV-infected children strongly indicate that genetic variants that alter the expression of functional CX3CR1 can profoundly influence the risk and rate of disease. Moreover, in multivariate analyses, a specific CX3CR1 genotype and haplotype strongly predicted both disease progression and CNS impairment independent of markers including CD4+ lymphocytes and plasma HIV-1 RNA load or CCR5-wt/Δ32, CCR5-59029-G/A and CX3CR1-T/M280 polymorphisms. Children with the wild-type V/V249 genotype that has been associated with greater binding to fractalkine when compared to the I/I249 genotype (28), experienced slower disease progression than children with the I/I249 genotype; however, the disease progression in V/I249 heterozygotes was similar to those with V/V249 genotype. For children with the CCR5-wt/wt genotype, we observed a significant association between the presence of the I/I249 genotype and an increased risk for impaired cognition. The same trend of increased risk was observed for children with the M/M280 genotype, albeit with a small number of children. Therefore, it would appear that genetic variants resulting in less CX3CR1 may place HIV-1 infected children at increased risk for CNS impairment.
Although much progress has been made in the development and implementation of strategies designed to interrupt MTCT, many women in developing countries still have limited access to antiretrovirals. The identification of genetic markers linked with transmission can help to define risk factors associated with MTCT and provide new insights into HIV-1 pathogenesis that can help in the development of an effective HIV-1 vaccine.
MTCT occurs predominantly with macrophage-tropic (M-tropic), non-syncytium inducing viruses that use CCR5 as a co-receptor (36), and up-regulation of CCR5 expression in the placenta is associated with vertical transmission (37). A decrease in CCR5 expression could negatively affect immunologic function in newborns and alter the risk of MTCT (38). Moreover, the 32-bp CCR5 deletion is absent in most African populations (39). Hence, other genetic variants that modify the expression or function of CCR5 or other HIV-1 co-receptors or modulators of innate immunity might alter the risk of MTCT. We examined the impact of CCR5 promoter, CCR2, CX3CR1 and SDF-1 polymorphisms on the risk of HIV-1 MTCT in three sub-Saharan African cohorts of infants. The study subjects were from Malawi, South Africa and Uganda. The Malawi and South Africa cohorts consisted of antiretroviral naïve pregnant women and their infants who were involved in vitamin A intervention trials that proved unsuccessful in reducing MTCT (40–42). For the Uganda cohort (HIVNET 012), mothers and their infants were randomly assigned to receive nevirapine or zidovudine (43). Nevirapine given to mother and baby significantly reduced MTCT compared to the zidovudine intervention. Overall, 21.4% of infants were determined to be HIV-1-infected, 20.2% of infants from Malawi, 24.7% from South Africa, and 19.8% from Uganda.
Our findings established a link between CCR5 promoter variants at positions 59029 and 59353 in infants and the risk for perinatal infection (44). Antiretroviral naïve infants with the 59029-A allele had a higher risk of MTCT versus G/G infants. Exposure to antiretrovirals modified the impact of these genetic variants on MTCT. Children with the CCR5-59029-A allele, which has been associated with higher expression of CCR5, were less likely to be infected when exposed to nevirapine (45). However, this same variant was associated with a higher risk for MTCT when zidovudine was given perinatally. Because CCR5-59029 and -59353 are in linkage disequilibrium, the associations between each of these polymorphisms and risk of transmission were similar. We speculate that the difference observed for MTCT between nevirapine and zidovudine exposed mother-infant pairs relates to the long half-life of nevirapine and its ability to rapidly decrease viral load. The effect of zidovudine on viral load was likely less than that of nevirapine and combined with its shorter half-life resulted in similar associations for zidovudine treated mother-infant pairs as for antiretroviral naïve infants. An alternative explanation for the effects observed with nevirapine and zidovudine on MTCT could be an unidentified differential modulation of the expression of chemokines or chemokine receptors that alter the risk for transmission or effect of other genetic factors (46, 47). A recent study reported the potential protective effects of CCR5-59029-G and -593563-T alleles against MTCT in Malawi children with lower maternal viral load (8, 48); however, this effect was lost in children with higher maternal viral load.
For the CCR5-59356-C/T promoter variant, infants with the T allele had a lower rate of transmission than infants with the C/C genotype. These findings differ from those of Kostrikis et al who reported that the presence of the T/T genotype was associated with a higher rate of MTCT in untreated mother-infant pairs in the United States (8). Although this may reflect geographic differences (Kostrikis et al evaluated mother-infant pairs from the United States while we studied the children from sub-Saharan Africa), this seems unlikely to be the explanation. Of interest, in a smaller cohort of Kenyan infants, John et al also found a trend toward decreased transmission associated with the 59656-T allele (49).
No significant effect of CX3CR1 genotypes on MTCT was observed in antiretroviral naïve mother-infant pairs. However, antiretroviral-exposed infants carrying the CX3CR1-745-A allele had a significantly higher rate of early transmission compared to infants with the G/G genotype that did not differ with nevirapine and zidovudine exposure.
Mangano et al (50) observed protective effects of CCR2-A/A genotype in Argentinean children born to HIV-1 infected mothers, while Teglas et al (51) and Brouwer et al(52) failed to find any impact of the CCR2 genotype on perinatal transmission in France and Western Kenya, respectively. In our study, the CCR2-A/A genotype was associated with higher risk of transmission versus G allele carriers suggesting a modest effect of CCR2 genotypes on MTCT in mother-infant pairs in sub-Saharan Africa.
The presence of SDF-1-G/A genotype in mothers was found to be associated with increased perinatal transmission of HIV-1 in Kenya in an earlier study (16). In our own studies, the presence of the SDF-1-A allele in infants was rare and no impact on MTCT could be identified. It is likely that if SDF-1-A alters MTCT that the relatively low frequency limits its impact on a population basis.
Much data support a role for the CC chemokines CCL3 (macrophage inflammatory protein [MIP]-1α), CCL4 (MIP-1β), and CCL5 (RANTES) in HIV-1 pathogenesis. In addition to chemotaxis, CC chemokines also play an important role in T-cell activation and in directing and enhancing adaptive immune responses. In humans, CCL3 protein is encoded by two functional genes (CCL3/LD78α and CCL3L1/LD78β), occurring as two copies and as variable copy numbers, respectively, in different individuals (53). CCL3 may mediate its protective effects through its ability to enhance adaptive immune responses. Research by Gonzalez and colleagues has shown that segmental duplications containing the gene encoding CCL3L1, a potent agonist and HIV-suppressive ligand for CCR5, is associated with variable chemokine expression, and risk of acquiring HIV and rates of disease progression (54). Of note, they identified that the number of CCL3L1 copies (gene dose) within a given population may vary and the risk of infection and rate of disease progression is dependent on the relative number of gene copies compared to the mean background for a given ethnic group. Meddows-Taylor et al identified a complex association between CCL3L1 copy numbers and MTCT (55). Infants born to HIV-infected mothers with lower levels of CCL3 production were at increased risk of infection and similarly, mothers who transmitted virus had low levels of CCL3. They also suggest that “…all CCL3-L1 gene copies are not created equal…” and that some duplications may not be as functional as others. In an extension of this group’s research, Kuhn et al (46) demonstrated a copy number dependent relationship between CCL3L1 gene duplication and MTCT in a cohort from South Africa. In this study, the mean number of copies per diploid genome was 4–5 with infants having fewer copies at greatest risk of infection and those with higher numbers at least risk.
As the immune system of children matures, changes occur in how both innate and adaptive immunity respond to microorganisms. Mannose-binding lectin (MBL) protein, encoded by the MBL2 gene, is an important determinant of the innate immune response during infection (56–59). MBL is an acute-phase protein that is synthesized by the liver and released into the bloodstream where it binds to the mannose residues present on some bacteria, yeast, viruses, and parasites. Binding activates the lectin complement pathway and production of C3b protein via MBL-associated serine proteases (MASPs) results in opsonization of pathogens, chemotaxis, activation of leukocytes, and direct pathogen killing (60). The MBL2 gene encodes 32 kD subunits which further associate to form high molecular weight (MW) MBL oligomers (60). MBL2 variants at the following nucleotide positions affect MBL levels: two single nucleotide polymorphisms at promoter positions -550-G/C (H/L variant) and -221-G/C (X/Y variant); one in the 5’ untranslated region +4-C/T (P/Q variant) and three genetic variants at codons 52, 54 and 57 in exon 1, at nucleotide positions 223-C/T (Arg52Cys, A/D allele), 230-G/A (Gly54Asp, A/B allele), and 239-G/A (Gly57Glu, A/C allele), respectively. MBL2 exon 1 variants result in single amino acid changes affecting oligomerization of MBL. Homozygous wt (A/A) sera contain predominantly fully functional MBL while homozygous mutant sera (any combination of B, C or D allele) contain mostly low MW MBL.
MBL deficiency has been identified as the cause of common opsonic defect of children. Additional studies have suggested that MBL plays a particularly important role in control of microorganisms in children ages 6–24 months when maternal IgG levels have waned and the infant’s own adaptive immune response is immature (56). Our studies in HIV-infected children indicate that the presence of the MBL2-O/O genotype that results in lower expression of MBL protein and impaired innate immunity is associated with more rapid development of CNS impairment in children (61). Similar to earlier studies of the association of MBL2 in HIV-1 infected adults (62–64), we observed an overall trend for a more rapid disease progression in children with variant MBL2 genotypes. However most strikingly, we observed significant associations between MBL2 variants and disease progression including cognitive impairment in children below 2 years of age. These findings are consistent with a critical role for MBL in the immune response of young children (65, 66). MBL deficiency has also been associated with increased HIV-1 vertical transmission (62), which emphasizes its important role in controlling HIV-1 infection in young infants and children.
HLA class I and class II alleles are the most polymorphic genes in humans and play a fundamental role in acquired immune responses. HLA types were among the first genetic markers found to alter the risk of becoming infected with HIV-1 and subsequent rate of disease progression (67, 68). Recently, in a case-cohort study of 572 HIV-infected children from PACTG 152 and 300, we assessed the impact of HLA class I and II alleles on HIV-related disease progression. Our preliminary findings have demonstrated that the presence of homozygous HLA-B or C alleles was associated with more rapid disease progression (unpublished, Singh and Spector). In contrast, the presence of B*27 or B*57 alleles was associated with slower disease progression which remained significant after adjustment for race, gender, age, and baseline HIV-1 log RNA, CD4+ count and percent and weight for age z-score or other genetic variants including CCR5-wt/Δ32, -59029-G/A, CCR2-wt/64I, CX3CR1-249-V/I, -280-T/M, SDF-1-180-G/A, MCP-1-G/A, MBL2-A/O, MBL2-X/Y, MBL2-P/Q, and MBL2-H/L. Additionally, the Cw-2 allele protected against disease progression and the A-24 allele was associated with more rapid CNS impairment. For HLA Class II, the presence of the DQB1*2 allele protected against HIV-1 disease progression and CNS impairment.
HLA has also been found to play an important role in MTCT. HLA concordance between a mother and her infant is associated with increased risk of transmission, while HLA discordance decreases the risk of MTCT (69, 70). Additionally, HLA class I homozygosity has been associated with more rapid disease progression (67, 68). Children homozygous or who have the same HLA class I alleles at both sites with their mothers at one of more HLA locus are at increased risk for more rapid disease progression (71).
A new class of host restriction factors has been found to play an important role in restricting intracellular viral replication. APOBEC3G (Apolipoprotein B mRNA Editing Catalytic Polypeptide 3G) formerly known as CEM15, is an endogenous inhibitor of HIV-1 replication (72). During permissive infection, APOBEC3G is incorporated into nascent virus particles and mediates deoxycytidine -to-deoxyuridine deamination of minus (first)-strand reverse transcripts in target cells. This results in guanine-to-adenine hypermutation of the viral plus (sense) coding strand and is associated with premature cDNA degradation. Thus, APOBEC3G limits the spread of HIV-1 infection by packaging into the virus during assembly. The potent antiviral activity of APOBEC3G is successfully neutralized by wild-type HIV-1 through vif by mediating its polyubiquitination and rapid degradation through the proteasome (73).
The importance of APOBEC3G-mediated antiviral response against HIV-1 is underscored by the existence of APOBEC3G genetic variants influencing disease progression. An APOBEC3G variant containing a non-synonymous substitution of Arg for His at amino acid position 186 is present in African-Americans and is strongly associated with more rapid decline of CD4+ T cells and accelerated progression to AIDS (73). Our preliminary studies (unpublished, Singh and Spector) in a cohort of more than 1000 children show that while H186R variants are associated with more rapid HIV disease progression, an F119F variant is associated with moderate protection against the HIV disease progression (74).
Interleukin-4 (IL4) differentially regulates the two major HIV-1 coreceptors -increasing CXCR4 and decreasing CCR5 expression in primary CD4+ T-lymphocytes. Homozygosity of a ‘C’ to ‘T’ polymorphism at the 589 nucleotide position in the IL4 promoter region (IL4-589-C/T), has been correlated with increased rates of SI variant acquisition in HIV-1-infected individuals in Japan (75). We examined the impact of IL4-589-C/T polymorphisms on HIV-1 disease in children. To our surprise, we found no association between the IL4-589-T allele and disease progression in any analyses performed (76). It is possible that the IL4-589-T allele may be in linkage disequilibrium with another allele not discovered so far, which affects disease progression in HIV-1 infected individuals. To date, however, no data exist to support a role for IL4 in HIV-1 disease of children.
Recently, the monocyte chemotactic protein-1 (MCP-1)-2518-G allele (associated with higher expression of MCP-1 than wild type 2518-A allele) has been shown to be associated with HIV-1–related disease (77). We hypothesized that if CCR2 (MCP-1 receptor) or MCP-1 variants were important in HIV-1 pathogenesis in children then combined CCR2-MCP-1 genotypes would be more likely to demonstrate such an effect than CCR2 alone. We found that the association of MCP-1-2518-G/G genotype with neurocognitive impairment at study entry was marginally significant (78). However, the presence of the MCP-1-2518-G allele independently or in combination with CCR2-64I allele did not impact overall progression of HIV-1 disease in children.
Several other host genetic factors affecting innate and adaptive immune responses can affect HIV-1 disease in children. These include apolipoprotein E, toll-like receptors (TLRs), DC-SIGN, IL-10, IL-6, IFN-γ, TNF-α, and CCR5 ligands MIP1α, or RANTES among others. Research is in progress examining the impact of these and other genetic variants on MTCT and HIV-1 disease progression in children.
Much research has established that host genetic factors are important determinants of HIV-1 MTCT and the rate of disease progression in children as well as adults. However, it is clear that no single genetic variant is a dominant factor in HIV-1 pathogenesis, and the risk for transmission and progressive immunosuppression depends on multiple interactions between virus and host. The judicious use of host genetics, however, has the potential to improve the care and treatment of HIV-infected pregnant women and children. In this regard, we have demonstrated that specific genetic variants are predictive of disease progression independent of a patient’s CD4+ lymphocyte count and viral load. Thus, the potential exists to develop a model of genetic variants that can be used as an adjunct to standard monitoring of T-cell subsets and plasma HIV-1 RNA to help guide when to start treatment. Although beyond the scope of this review, genetic variants in CYP genes and ABCB1 have been shown to alter the pharmacokinetics and response to specific antiretrovirals and can be used to optimize treatment of children (79, 80). Moreover, the HLA-B5701 allele is associated with the hypersensitivity reaction associated with abacavir. Screening for this allele has become standard of care for persons prior to initiating antiretroviral therapy containing abacavir (81). Perhaps most importantly studies of host genetics provide new insights into innate and adaptive immunologic mechanisms used to control HIV-1 infection. These findings can lead to improved understanding of how each arm of the immune system orchestrates an integrated, albeit insufficient, response to viral infections. It is likely that these approaches will lead to novel new strategies for vaccine development. In this regard, we believe that a successful HIV-1 vaccine will come when we are able to “educate” innate immunity such that the virus is controlled prior to establishing infection. Understanding host-virus interactions will be critical to these potential breakthroughs.
The authors acknowledge the outstanding statistical support of Terrence Fenton, Michael Hughes, Ping Ruan and Jie Chen, the technical assistance of Rodney Trout, the many clinical investigators who have allowed us to use specimens and outcome data from their clinical studies, the study participants and their families, the Pediatric AIDS Clinical Trials Group (PACTG) and the International Maternal Perinatal Adolescent Antiretroviral Clinical Trials (IMPAACT) Network.
Financial Support: Supported by Grants from the National Institute of Allergy and Infectious Diseases, The International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) Network (AI-069536).