HLA markers associated with progression to AIDS are also associated with susceptibility to cytomegalovirus retinitis
Fernandes, Ana Paula Ma; Gonçalves, Maria Alice Gb; Zavanella, Raquel Ba; Figueiredo, José Fernando Cb; Donadi, Eduardo Ab; Rodrigues, Maria Lourdes Vb
aSchool of Nursing of Ribeirão Preto, and bSchool of Medicine of Ribeirão Preto, University of São Paulo, 14 049-902, Ribeirão Preto, SP, Brazil.
Sponsorship: This work received financial support from FAPESP (01/02908-2 – M.A. Gonçalves), and CNPq (35 0541/1994-9-M.L.V. Rodrigues).
Received: 19 March 2003; revised: 24 April 2003; accepted: 28 April 2003.
The frequency of HLA markers associated with rapid progression from HIV infection to AIDS was evaluated in Brazilian patients with AIDS exhibiting or not exhibiting cytomegalovirus retinitis (CMV-R). A total of 124 AIDS patients (44 with and 80 without CMV-R) were studied. HLA markers associated with rapid progression to AIDS were significantly increased in the CMV-R group compared with those without retinitis. The presence of these HLA markers may simultaneously predispose to AIDS and CMV-R.
Several genetic markers are associated with progression to AIDS and, to a lesser extent, others are associated with resistance to HIV infection [1–3]. AIDS epidemicity is characterized by extreme heterogeneity in terms of the clinical course and variable incidence of HIV-1 infection among exposed individuals [4,5]. These findings probably reflect the genetic variants of HIV-1 strains and host genetic polymorphic genes, including chemokine and chemokine receptor structural genes [6–9] and HLA alleles [10,11]. The progression from HIV-1 infection to AIDS has been strongly associated with HLA-A1-Cw7-B8-DR3-DQ2 and HLA-A11-Cw4-B35-DR1-DQ1 haplotypes, conferring a high risk of rapid progression to AIDS [12–14]. On the other hand, HLA-Bw4, B44 and B57 allele groups have been associated with restriction to virus replication in a subset of HIV-infected long-term non-progressors [15–17]. It has been assumed that associations between the progression to AIDS and particular HLA alleles reflect differential antigen presentation by classes I or II molecules exhibiting particular motifs in the peptide binding groove .
Cytomegalovirus is an important opportunistic infectious agent in AIDS patients that may cause considerable morbidity. Cytomegalovirus retinitis (CMV-R) develops in approximately 28–35% of all AIDS patients at later stages of the disease and often leads to blindness . HIV-infected individuals presenting with HLA-A2, B44, B51, DR4 and DR7 antigens have low T-cell immune responses to cytomegalovirus and are predisposed to CMV-R and encephalitis as the immunodeficiency progresses [20,21]. In a previous study on Brazilian patients with AIDS presenting with CMV-R or not, no particular association with HLA class I or II specificities was found; however, HLA-A31 antigen was overrepresented in AIDS patients irrespective of CMV-R . To explore further whether HLA markers, which have been described in association with rapid or slow progression to AIDS, may be associated with the development of CMV-R, we evaluated these markers in Brazilian AIDS patients presenting with CMV-R or not.
The study was conducted on 124 adult HIV-infected patients (81 men) aged 21–59 years (median 33) presenting with AIDS, diagnosed 1–108 months (median 22) before inclusion in the study. These patients presented with zero to eight episodes (median 3) of opportunistic infections. Forty-four patients experienced CMV-R, confirmed by retinal examination by a trained ophthalmologist, with focus on indirect binocular ophthalmoscopy, and the remaining patients did not present with CMV-R after a 2-year follow-up.
HLA class I antigens were typed using a microlymphocytotoxity assay , and HLA class II alleles were characterized using polymerase chain reaction (PCR)-amplified DNA hybridized with sequence-specific oligonucleotide probe or sequence-specific primer analysis using commercial kits (One Lambda, Canoga Park, CA, USA, and Ruprecht-Karls-Universität, Heidelberg, Germany), as previously described .
As HLA-A1, A11, B8, B35, DR3, DR1, DQ2, DQ1 antigens are associated with rapid progression to AIDS [12–14] in many ethnic groups, these markers were considered for analysis in the present study. HLA-Bw4, B44, B57 antigens are associated with slow progression to AIDS [15–17], and were also considered for analysis in the study.
Fisher′s exact test was used and was considered to be significant at P < 0.05. The relative risk (RR) and the aetiological fraction (EF) were also calculated to estimate the strength of the associations .
Seventy patients (56.4%) exhibited at least one of the described HLA markers associated with rapid progression to AIDS. Among these markers, HLA-B35 and DQ2 were the most frequent, being observed in 44.3% (31/70) and 54.3% (38/70) of the patients, respectively. On the other hand, nine patients presented with at least one marker associated with slow progression to AIDS (7.2%), and 19 patients presented with both rapid and slow progressor markers (15.3%). Twenty-six patients presented with no rapid or slow progressor markers (21%).
Forty-four patients presented with CMV-R, 33 of whom (75%) possessed at least one of the HLA markers associated with rapid progression to AIDS. Eighty patients did not present with CMV-R, 37 of whom (46.2%) exhibited at least one of the HLA markers associated with rapid progression to AIDS. The frequency of the markers associated with rapid progression to AIDS was significantly increased in patients with CMV-R in relation to those without retinitis (P < 0.002), conferring a RR of 1.6 and an EF of 0.281. Moreover, the combined frequency of the HLA-DQ2 and HLA-B35 markers among patients presenting with CMV-R was significantly increased in relation to those without it (P < 0.04), conferring a RR of 1.7 and an EF of 0.177 (Table 1).
The extraordinary polymorphism of HLA alleles is maintained through selective forces induced particularly by infectious agents, which have been associated with high rates of morbidity and mortality [26,27].
More than 50 reports examining the role of HLA specificities in AIDS susceptibility have been published , and the haplotypes encompassing HLA-B35 antigens are consistently associated with rapid progression to AIDS in several populations . In a previous study conducted by us  the frequency of the HLA-A31 antigen was significantly increased in AIDS patients presenting or not with CMV-R, indicating that the marker was associated with AIDS and not with the presence of CMV-R. As the Brazilian population shows high genetic diversity, the lack of association with CMV-R may be caused by the large extent of the HLA polymorphism. On the other hand, when we compared the frequencies of HLA markers that have been associated with rapid progression to AIDS in several populations, these markers were overrepresented in AIDS patients (75% in patients with and 46.2% in those without CMV-R), indicating that, with the development of CMV-R, the frequency of HLA markers associated with rapid progression to AIDS increases. As the frequency of cytomegalovirus infection is high in Brazilian AIDS patients, reaching a value of 98% , and as CMV-R is manifested during the most advanced stages of the immunodeficiency, HLA markers associated with rapid progression to AIDS may represent additional risk factors for the development of CMV-R, and suggest that these patients may present with CMV-R within a shorter period of time in relation to patients without the markers.
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