Print version ISSN 1413-8670
Braz J Infect Dis vol.14 no.5 Salvador Sept./Oct. 2010
Edinete Melo da SilvaI,II; Angelina Xavier AcostaII,III; Eduardo José Melo SantosIII; Eduardo Martins NettoI; Denise Carneiro LemaireIV; Adriano Silva OliveiraI; Carolina Matos BarbosaV; Maria Teresita BendichoIV; Bernardo Galvão-CastroII; Carlos BritesI
IInfectology Research Laboratory of Hospital Universitário Professor Edgard Santos - HUPES -UFBA, Brazil
IIAdvanced Laboratory of Public Health - LASP/CPQGM/FIOCRUZ, Brazil
IIIDepartment of Pediatrics, , School of Medicine, UFBA, Brazill
IVLaboratory of Immunology of Instituto das Ciências e Saúde - ICS/UFBA, Salvador-BA, Brazil
VLaboratory of Humam and Medical Genetics, Biological Sciences Center, UFPA, Belém - PA, Brazil
Host genetic factors play an important role in mediating resistance to HIV-1 infection and may modify the course of infection. HLA-B alleles (Bw4 epitope; B*27 and B*57) as well as killer cell immunoglobulin-like receptors have been associated with slow progression of HIV-1 infection.
OBJECTIVE: To evaluate the association between serological epitopes HLA-Bw4 and HLA-Bw6 and prognostic markers in AIDS.
METHODS: 147 HIV-infected individuals in Bahia, Northeast Brazil, were genotyped for HLA class I locus. HLA class I genotyping was performed by hybridization with sequence-specific oligonucleotide probes following amplification of the corresponding HLA-A, HLA-B and HLA-C genes. Statistical analysis was performed using Fisher's exact and ANOVA tests for categorical and continuous variables, respectively.
RESULTS: We detected a significant association (χ2 = 4.856; p = 0.018) between the presence of HLA-Bw4 and low levels of viremia. Eighteen out of the 147 HIV-infected individuals presented viremia <1,800 copies/mL and 129 presented viremia > 2,000 copies/mL. Ninety and four percent (17/18) of all individuals with viremia < 1,800 copies/mL carried HLA-Bw4, compared to 67.4% (87/129) of individuals with viremia > 2,000 copies/mL. Additionally, we found a significantly higher frequency of B*57 (OR = 13.94; 95% CI = 4.19-46.38; p < 0.0001) and Cw*18 (OR = 16.15; 95% CI = 3.46-75.43; p < 0.0001) alleles, favoring the group with lower viremia levels, in comparison with those with higher viral load.
CONCLUSION: HLA-Bw4-B*57 and Cw*18 alleles are associated with lower level of viral load in HIV-infected Brazilian patients. These findings may help us in understanding the determinants of HIV evolution in Brazilian patients, as well as in providing important information on immune response correlates of protection for such population.
Keywords: HIV, AIDS, MHC, HLA, polymorphism.
The dynamics of HIV-1 replication is a very important factor in determining the clinical course of HIV-1 disease. Although an enhanced production of virus particles results in progressive deterioration of the immune system in most HIV-1 infected individuals, the control of viremia and the rate of progression of HIV-1 disease have been demonstrated to be substantially influenced by host genetic characteristics.
The genetic profile of human leukocyte antigen (HLA) class I molecules plays a very important role in both, the innate and adaptative immune responses during the course of HIV-1 infection. Cytotoxic T lymphocyte (CTL) response depends on the recognition of viral peptides presented in association with major histocompatibility (MHC) class I molecules on the surface of infected cells.1 Certain types of HLA-B alleles, especially B*27 and B*57, seems to strongly influence AIDS progression.2-6 HIV-specific CTL play a central role in the initial control of virus replication during primary HIV infection, when the immunologic response limits the viral replication and reduces the viremia and the number of infected cells in lymph nodes,7-10 as well as during chronic HIV infection, since the high number of HIV-specific CTL often persists in late infection in peripheral blood of HIV-infected patients.11,12 Several studies reported that in HIV-infected long-term survivors the viral load and the number of CD4+ T cells infected with HIV-1 are very low, and a strong HIV-specific CTL response is detected during the course of infection.13,14
The HLA repertoire can be implicated in the innate immunity responses. HLA class I molecules have been identified as killer immunoglobulin receptor (KIR) ligands.15,16 In particular, all HLA-B specificities are grouped in two antigenic families: HLA-Bw4 and HLA-Bw6.17 HLA-Bw4 and HLA-Bw6 epitopes consist of a single epitope in each HLA-B molecule and they are different from the epitopes that establish the HLA-B specificity; therefore each HLA-B molecule expresses only one of the serological epitopes HLA-Bw4 or HLA-Bw6. HLA-Bw4 is one of the inhibitory or activating ligands for KIR18,19 that control the natural killer (NK) cell cytotoxic activity. As a component of the innate immune system NK cells might have a very important role in the defense of the HIV-1 infected host,20 possibly controlling the viremia through lysis of HIV-infected cells.21,22 Genetic association studies and functional assays report the importance of HLA-Bw4 in the pathogenesis of AIDS. Two studies have shown the protective role of HLA-Bw4 against HIV-disease progression through association with viremia control and CD4+ T cell count maintenance.21,23 Qi et al24 reported the synergistic role of KIR3DS1/Bw4-80Ile against CD4+ T cell depletion and development of opportunistic infections. A more recent study has demonstrated that the presence of HLA-Bw4 is associated with a decreased risk in male-to-female HIV-1 transmission.25 The objective of this study was to evaluate the association between serological epitopes HLA-Bw4 and HLA-Bw6 and the modulation of viral load and CD4+ T cell count in the Brazilian HIV-infected patients.
MATERIAL AND METHODS
Were evaluated 147 HIV-infected individuals, selected from an AIDS cohort established at the Hospital Universitário Professor Edgard Santos (HUPES) and Centro de Referência Estadual de AIDS (CREAIDS) in 1997 with HIV positive patients from the state of Bahia, Northeast Brazil. All the patients had a Western Blot-confirmed HIV-1 infection. The cohort was monitored for CD4+ and CD8+ T cell count (cells/mm3) and plasma viral load (copies/mL) every six months. The demographic and clinical parameters of all patients are summarized in Table 1. In Bahia state, there is a great genetic mixture of Portuguese and African descendents.26-28 Informed consent for blood donation and for genetic polymorphism investigation was obtained from each patient. This study was approved by the Comitê de Ética em Pesquisa do Centro de Pesquisa Gonçalo Moniz, Process # 29/2003.
A subset of the patients (18 individuals) was classified as viremia controllers, in accordance with the HIV Controller Consortium.29 All controllers had been infected for more than two years, remained asymptomatic during the follow up without antiretroviral therapy and maintained the viral load < 1,800 copies/mL. The patients that did not attained to all these criteria (129 individuals) were classified as viremia non-controllers.
HLA and KIR genotyping
Genomic DNA was extracted from whole blood using extraction method GFXTM Kits Genomic Blood DNA Purification (Amersham Pharmacia Biotech, UK). HLA genotyping was performed by using SSO LABType(R) method (ONE LAMBDA, Inc., Canoga Park, USA) according to the manufacturer's instructions. Briefly, the polymerase chain reaction (PCR) conditions were: 96ºC for 3 minutes, followed by 5 cycles of 96ºC for 20 seconds, 60ºC for 20 seconds and 72ºC for 20 seconds, and 30 cycles of 96ºC for 10 seconds, 60ºC for 15 seconds and 72ºC for 20 seconds, and extend at 72ºC for 10 minutes. After amplification of genomic DNA using locus-specific primers that flanked exon two and three, PCR products were denatured and annealed to sequence-specific oligonucleotide (SSO) probes of the corresponding HLA-A, -B and -C genes. The fluorescent intensity of binding probes was identified by LABScanTM100 flow analyzer and the results were interpreted using HLA-visual software that established the HLA genotyping. HLA-A and HLA-B alleles were pooled HLA-Bw4 and HLA-Bw6 according to HLA class I sequence alignments30 (Table 2). KIR3DS1 and KIR3DL1 genotyping was performed by using gene-specific primer pairs according to Martin et al.21 Each reaction contained 15 ng of DNA, 0.1 mM DNTPs, 1.5 mM MgCl2, 67 mM Tris-HCl (pH 8.8), 16 mM (NH4)2SO4, 0.25 mM of each primer, and 1U of Taq polymerase in a 10 µL final volume. To improve the reliability of the results, besides the utilization of an internal control, all negative reactions were repeated to confirm non-amplification in the PCR. In addition, positive results were randomly replicated. Phenotype frequencies (f) for the presence of each gene were estimated by direct counting.
Mean viral load and CD4+ T cells count for each patient (before starting antiretroviral therapy) was estimated and used as representative value in the statistical analysis. ANOVA and Mann-Whitney tests were used to compare continuous variables. Fisher's exact test was used to investigate associations between categorical variables and correction for multiple tests was applied when necessary. Hardy-Weinberg Equilibrium analysis was performed for each population (controllers and non-controllers of viremia) using Genepop software.31 Additionally, Odds Ratio (OR), and their 95% confidence interval was used to determine the strength of the allele-specific associations that were statistically significant.
We detected a direct correlation between viral load and CD4+ T cell count, fundamental markers for HIV-infected patient monitoring. It was statistically significant (R = -0.307; p < 0.001, by Pearson's correlation) and the regression analysis suggested there was a logarithmic relationship between both variables.
Effects of HLA-Bw4 on viral load and CD4+ T cell count modulation
Viral load averages for Bw4, Bw4/Bw6 and Bw6 phenotypes are shown in Figure 1, which emphases the increasing gradient from absence of HLA-Bw6 to presence of HLA-Bw4. ANOVA test showed a borderline significant difference between and within the groups that was lost after correction (p = 0.059; pc = 0.076) (Table 3). The categorization into Bw4+(Bw4/Bw/4 and Bw4/Bw6) and Bw4-(Bw6/Bw6) patients groups yielded a more significant association. Mann-Whitney test revealed a statistically significant difference between Bw4+and Bw4-groups, suggesting an association of the presence of HLA-Bw4 with viral load reduction (Z = -2.052; p = 0.040) (Table 3). Additionally, we observed that 18 out of the 147 HIV-infected individuals presented viremia < 1,800 copies/mL and 129 presented viremia > 2,000 copies/mL. Ninety four percent (17/18) of all individuals with viremia < 1,800 copies/mL carried HLA-Bw4, compared to 67.4% (87/129) of individuals with viremia > 2,000 copies/mL (Table 4). We detected a statistically significant association (OR = 8.21; 95% CI = 1.08-63.76; p = 0.018; Fisher's exact test) between the presence of HLA-Bw4 and low levels of viremia.
The same comparative analysis used for viral load was used for CD4+ T cell count average (Figure 2). Although individuals presenting Bw4+had a higher mean CD4+ T cell count than individuals not presenting this allele, the comparison of the groups revealed no significant association between the presence of HLA-Bw4 and higher CD4+ T cell count (p = 0.282), even after stratifying patients into Bw4+(Bw4/Bw/4 and Bw4/Bw6) and Bw4-(Bw6/Bw6) groups (Z = 1.220; p = 0.222) (Table 3), suggesting no influence of HLA-Bw4 on CD4+ T cell count modulation.
Protective B*57 and Cw*18 alleles in the viremia controller
HLA class I alleles play a role in the biology of both NK and CTL responses, in the control of viral load levels. To evaluate the influence of HLA class I alleles in viremia control we compared the frequencies of HLA-A, HLA-B, and HLA-C alleles for viremia controller and non-controller groups. No significant deviations from Hardy-Weinberg equilibrium were found in all loci analyzed: HLA-A (p = 0.33), HLA-B (p = 0.34), and HLA-C (p = 0.30). No statistically significant difference for HLA-A allele frequencies was found between the groups (p = 0.828) (Table 4). However, we detected a significant difference in the B*57 (OR = 13.94; 95% CI = 4.19-46.38; p < 0.0001) and Cw*18 (OR = 16.15; 95% CI = 3.46-75.43; p < 0.0001) allele frequencies, which were relatively more frequent in the viremia controller than in non-controller group (Table 4). These data suggest a protective role of the B*57 and Cw*18 alleles in the control of viral load. Curiously, 100% of Cw*18 carriers (5/5) that control the viremia are also B*57 carriers, while this last allele was found in 66.7% (2/3) of the non-controller group.
Influence of HLA-B*57 allele in the protection conferred by HLA-Bw4
Genetic and functional studies have shown a protective effect of HLA class I alleles, in particular B*27 and B*57, in the HIV disease progression. These alleles belong to the HLA-B Bw4 group. In order to evaluate the effects on NK and CTL responses to that regard, we analyzed the role of HLA-Bw4 on HIV disease progression markers in the presence and absence of B*27 and B*57 alleles. The protective effect of HLA-Bw4 remained significantly upon removal of the individual positive for B*27 (p = 0.044), but was entirely lost in the absence of B*57 (p = 0.201) (Table 3), indicating that the protection conferred by HLA-Bw4 is completely dependent on the presence of B*57.
Effects of KIR3DS1/3DL1 on viral load and CD4+ T cell count modulation
HLA-Bw4 molecules with isoleucine at position 80 (Bw480Ile) are ligands for inhibitory KIR3DL1 receptors and Bw4-80Ile in combination with the activating KIR3DS1 found to result in delayed progression to AIDS. To assess the effect of the alleles Bw4-80Ile,KIR3DL1 and KIR3DS1 on viral load and CD4+ T cell count modulation we analyzed their distribution in this population. Initially, we compared the viral load and CD4+ T cell average between the patients Bw4-80Ile+(80Ile/80Ile or 80Ile/80Thr) and Bw4-80Ile-(80Thr/80Thr) (Table 3). We observed a non protective influence of Bw4-80Ile on viral load (p = 0.687) or CD4+ T cell count (p = 0.687) modulation. Next, we compared the frequencies of Bw4-80Ile and Bw4-80Thr in the viremia controllers and non-controllers groups (Table 4). We found no statistically significant difference between the groups (p = 0.790). This result may suggest that the association of HLA-Bw4 with viral load reduction in the HIV-1 infection found here is not specifically attributed to the Bw4-80Ile. The influence of KIR3DL1 and KIR3DS1 subtypes on clinical markers modulation was also tested: KIR3DL1 and KIR3DS1 were carried by 72.8% (107/147) and 21.8% (35/147) of patients, respectively. Eight patients (5.4%) who were negative for KIR3DL1 and KIR3DS1 were not included in the analysis (Table 3). We did not find any significant association between the presence or absence of KIR3DL1/KIR3DS1 genotype and the clinical markers of HIV-1 infection (Tables 3 and 4). We observed that all patients who carried protective B*57 and Cw*18 (B*57 = 15/147; B*57-Cw*18 = 7/15; Cw*18 = 8/147) alleles also carried KIR3DL1, but carried no KIR3DS1. These data suggest no effect of KIR3DS1/3DL1 genotype on viral load and CD4+ T cell count modulation.
Previous findings have shown the important role of cellular immunity in controlling HIV-1 replication.8,10,11,32 HIV-specific CTL, selected according to HLA class I repertoire associated to viral peptides, can control the viral replication efficiently through lysis of infected cells before new viral particles arise.14 In this study HLA-A and HLA-B alleles were grouped according to serological antigens HLA-Bw4 and HLA-Bw6 (Table 2). Some studies have reported the important influence of HLA-Bw4 in HIV-1 pathogenesis. Martin et al (2002) demonstrated epistatic interaction between KIR3DS1/Bw4-80Ile and delayed progression to AIDS by genetic analysis.21 Qi et al have demonstrated that KIR3DS1/Bw4-80Ile genotype is involved directly in the protection against HIV-1, controlling the viral load through lysis of infected cells, and/or indirectly preventing or delaying the onset of opportunistic infections.24 This corroborates our findings.
Here, we observed an association between HLA-Bw4 and viral load reduction. The HLA-Bw4 phenotype seems to modulate the viral load levels, when considering the whole infected population (Figure 1 and Table 3). Ninety four percent of these patients, who consistently presented viral load levels < 1,800 copies/mL, during a period of 2 to 12 years without antiretroviral therapy, carried HLA-Bw4, which confirms the protective role of this specific allele for HIV-infected individuals. However, the protective influence of HLA-Bw4 on the control of viremia is completely dependent on the presence of B*57 allele (Table 3), a finding that confirm the already reported favorable effect of B*57 on HIV-1 viral load.6
Beyond the B*27 and B*57, HLA-C alleles can play an important role in the HIV/AIDS context. Lazaryan et al have demonstrated that Cw*18 allele is associated with lower viral load among all subjects with and without B*5703 in the Zambian cohort.33 In our study, 27.8% of the viremia controllers individuals carried Cw*18 allele, which was significantly associated with lower viral load levels, suggesting a protector effect on HIV-1 infection in this population. As 100% (5/5) of controllers of viremia individuals who carried Cw*18 also carried B*57 and these alleles are in linkage disequilibrium it is possible to attribute the protective effect of Cw*18 to the presence of B*57. Theoretically, the role of Cw*18 and HLA-Bw4/B*57 may be independent, although it can be involved in the same context to produce effective NK and CTL responses.
HLA-Bw4 epitope and HLA-C allotypes are ligands for NK cell receptors KIR3DL1/3DS1 and KIR2DL1/2DL2/2DL3, respectively34 and stimulate its cytotoxic activity that is complementary to CTL responses. Inhibitory KIR3DL1 and activating KIR3DS1 receptors can play a protective effect on AIDS progression in the presence of HLA Bw4-80Ile ligand in the infected cell.21,35 Inhibitory KIR3DL1 allele highly expressed on the cell enhance protection conferred by HLA Bw4-80Ile allele, including B*57 specifically.35 In our work HLA Bw4-80Ile, KIR3DL1 and KIR3DS1 alleles had no influence in the modulation of clinical markers in HIV-1 infection, even in face of high KIR3DL1 (72.8%) and moderate KIR3DS1 (21.8%) expression.
Involvement of Cw*18 in NK cell activity will not be discussed here because we did not verify the distribution of KIR2DL(1-3) receptors to HLA-C allotypes, and therefore it is beyond the scope of this work. We cannot define the exact mechanism by means both populations of T lymphocytes (CTL and NK) might modulate the virus level in favor of the host. However, once the pivotal role of CTL is influenced by the HLA profile, we could suggest that the allelic groups of HLA-B that compound the HLA-Bw4 group and HLACw*18 allele are specific and more efficient in presenting peptides of circulating viral variants in this population, being able to produce an effective cellular immune responses. In addition, according to our results, it is possible to suggest that HLA-Bw4 and HLA-Cw*18 might function as activators of NK cell cytotoxic activity to destroy HIV-infected cells, which represent one of the main viral reservoirs. As a consequence of the destruction of these reservoirs mediated by combined CTL and NK activity, the plasmatic viral levels would decrease. Obviously, functional assays would be necessary to confirm this hypothesis.
Our data not only confirm the findings of other studies, in different populations, but also reinforce the important influence of the MHC polymorphisms in HIV/AIDS natural history, regardless the ethnic groups. It is very important to emphasize that the Brazilian urban populations are quite heterogeneous in terms of ethnic/genetic structure, and unique (a wide genetic mixture involving Amerindians, Portuguese and Africans),26-28,36 when compared to other populations around the world. Bahia, in particular, has a bigger genetic contribution of Africans and Portuguese,26-28 what becomes genetically different of the populations from other regions of Brazil. Additionally, environmental factors involved in HIV infection, such as social-economic and cultural factors, are also particular to this specific Brazilian region (Bahia), which resembles African countries, not only due to its genetic composition but also to social structure, culture, and health problems.28,37 Therefore, we could deduce that the profile of the association found here will be able to serve as orientation foretells for politics of public health, with reference to infection/illness prevention, and that the HLA profile of the studied patients can be used for therapeutic monitoring in order to improve the effectiveness of the AIDS treatment.
HLA-Bw4-B*57 and Cw*18 alleles are associated with lower level of viral load in HIV-infected patients from Bahia. This is the first study to demonstrate that serological epitopes HLA-Bw4 and HLA class I alleles are associated with disease progression markers in HIV-1 infection involving patients from Bahia, and provides important information about how the host genetic factors influence the AIDS clinical course.
Taken together, these findings may help us in understanding the determinants of HIV evolution in Brazilian patients, as well as in providing important information on immune response correlates of protection for such population. The prevention of the AIDS development in the Bahia population will reduce the costs with medicines that are necessary for who has already developed the disease. However, it is necessary to confirm these data through a study with a larger number of samples.
We thank the HUPES and CREAIDS outpatient clinics, and all the patients for their participation in this study.
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Edinete Melo da Silva
Laboratório de Pesquisa em Infectologia, Hospital Universitário Professor Edgard Santos
Rua Augusto Viana, S/N-Canela, , 6º andar
Salvador - Bahia - Brazil CEP: 40110-060
Phone: +55-71-32838126; Fax: +55-71-32472756
Submitted on: 3/4/2010
Approved on: 5/21/2010
We declare no conflict of interest.
This study was financially supported by Fundação de Amparo a Pesquisa do Estado da Bahia (FAPESB), Salvador, Bahia, and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq/PAPES), Brazil.