Biomedical subjects

Renu B Lal

Publications and source records attributed to Renu B Lal.

At least 19 recordsLinked to original sources

PubMed2005

theta-Defensin pseudogenes in HIV-1-exposed, persistently seronegative female sex-workers from Thailand.

The leukocytes of rhesus monkeys contain cyclic octadecapeptides (theta;-defensins) that can protect cells from infection by HIV-1 in vitro. Although humans express mRNA from one or more theta;-defensin pseudogenes, these transcripts contain a premature stop codon that prevents formation of theta;-defensin peptides. We hypothesized that some highly exposed persistently seronegative (HEPS) individuals might have intact theta;-defensin (DEFT) genes and produce functional theta;-defensins that might account for their resistance to HIV-1 infection. We sequenced DEFT genes from 30 women in Chiang Rai, northern Thailand: 11 HEPS female sex-workers and 19 control women (10 HIV-1 infected and 9 HIV-1 uninfected). We found that theta;-defensin genes from all 11 HEPS women contained the crucial signal sequence stop codon, as did the 19 control women. Synthetic theta;-defensins based on the cDNA sequences to generate a human theta;-defensin (termed retrocyclin-1 and -2) were capable of inhibiting replication of Thai HIV-1 subtype B and CRF01_AE isolates regardless of the coreceptor utilization of the isolates. Although our study indicates that synthetic theta;-defensin peptides are effective in vitro against Thai subtype B and CRF01_AE isolates of HIV-1, the presence of premature stop codons in the DEFT genes of these HEPS women makes it unlikely that endogenous theta;-defensin production accounts for their resistance to HIV-1.

Amino Acid Sequence↗

PubMed2005

Association of CCR5 human haplogroup E with rapid HIV type 1 disease progression.

The combination of unique single nucleotide polymorphisms in the CCR5 regulatory and in the CCR2 and CCR5 coding regions, defined nine CCR5 human haplogroups (HH): HHA-HHE, HHF*1, HHF*2, HHG*1, and HHG*2. Here we examined the distribution of CCR5 HH and their association with HIV infection and disease progression in 36 HIV-seronegative and 76 HIV-seropositive whites from North America and Spain [28 rapid progressors (RP) and 48 slow progressors (SP)]. Although analyses revealed that HHE frequencies were similar between HIV-seronegative and HIV-seropositive groups (25.0% vs. 32.2%, p > 0.05), HHE frequency in RP was significantly higher than that in SP (48.2% vs. 22.9%, p = 0.002). Survival analysis also showed that HHE heterozygous and homozygous were associated with an accelerated CD4 cell count decline to less than 200 cells/microL (adjusted RH 2.44, p = 0.045; adjusted RH = 3.12, p = 0.037, respectively). These data provide further evidence that CCR5 human haplogroups influence HIV-1 disease progression in HIV-infected persons.

Acquired Immunodeficiency Syndrome↗

PubMed2005

Effect of CCR2 chemokine receptor polymorphism on HIV type 1 mother-to-child transmission and child survival in Western Kenya.

The effect of CCR2 polymorphism on HIV-1 mother-to-child transmission and disease progression has not been explored in depth within Africa. As the CCR2-64I variant of this putative HIV coreceptor has been associated with slower progression to AIDS in adults, the current study was undertaken to examine the relationship between CCR2 polymorphism and HIV-1 perinatal transmission and child survival in western Kenya. CCR2 genotype was determined for 445 HIV-seropositive mothers and their infants. The CCR2-64I allele frequency of both mothers and children did not differ by HIV-1 transmission status, regardless of maternal viral load, viral subtype, immune status, or placental malaria status. For infants who acquired HIV perinatally (n = 78), there was no association between CCR2 genotype and viral load upon infection or survival rate over the 2-year follow-up. Our results do not indicate an effect of CCR2-64I on perinatal HIV transmission and survival in Kenyan children.

Disease Progression↗

PubMed2005

Genetic diversification and recombination of HIV type 1 group M in Kinshasa, Democratic Republic of Congo.

As the HIV-1 pandemic becomes increasingly complex, the genetic characterization of HIV strains bears important implications for vaccine research. To better understand the molecular evolution of HIV-1 viral diversity, we performed a comparative molecular analysis of HIV strains collected from high-risk persons in Kinshasa, Democratic Republic of Congo (DRC). Analysis of the gag-p24, env-C2V3 and -gp41 regions from 83 specimens collected in 1999-2000 revealed that 44 (53%) had concordant subtypes in the three regions (14 subsubtype A1, 10 subtype G, 8 subtype D, 5 subtype C, 2 each subsubtype F1 and CRF01_AE, and one each of subtypes H and J, and subsubtype A2, while the remaining 39 (47%) had mosaic genomes comprising multiple subtype combinations. Similar multisubtype patterns were also observed in 24 specimens collected in 1985. Sequence analysis of the gag-pol region (2.1 kb) from 21 discordant specimens in the gag-p24, env-C2V3 and -gp41 regions in 1985 and 1999-2000 further confirmed the complex recombinant patterns. Despite the remarkable similarity in overall subtype distribution, the intra- and intersubtype distances of major subtypes A1 and G increased significantly from 1985 to 1999-2000 (p=0.018 and p=0.0016, respectively). Given the complexity of HIV-1 viruses circulating in DRC, efforts should focus on the development of vaccines that result in cross-clade immunity.

Democratic Republic of the Congo↗

PubMed2005

HIV type 1 sequence diversity and dual infections in Kenya.

As vertical transmission of HIV-1 is an ongoing problem in East Africa, we analyzed HIV-1 strains of infected mothers, from Kisumu, Kenya. We sequenced the gag and gp120 regions from peripheral blood mononuclear cells (PBMC) of 15 HIV-infected mothers attending an antenatal clinic. PCR, cloning, bootscanning, using the program Simplot, and phylogenetic analyses were conducted to assign subtypes and identify recombinants. Our analyses showed two dual infections from patients who had infections with pure subtypes and recombinants subtype D. In addition, we also noted the presence of subsubtype A1 and A2, as well as unique recombinants in this area. These results imply that the HIV epidemic in western Kenya is a dynamic one and is continually evolving. Therefore, continued monitoring of the epidemic in this region is necessary if a vaccine for the area is to be developed.

Female↗

PubMed2005

Impact of genetic diversity of HIV-1 on diagnosis, antiretroviral therapy & vaccine development.

HIV-1 strains have diversified extensively through mutation and recombination since their initial transmission to human beings many decades ago in central Africa. The high error rate of HIV reverse transcriptase combined with the estimated in vivo HIV-1 replication rate of ten billion new virions each day leads to extraordinary genetic diversity of HIV. Twenty seven circulating genetic forms of the HIV-1 group M are presently recognized, including 11 subtypes and sub-subtypes, and 16 circulating recombinant forms (CRF). Genotypic analyses have provided a better understanding of the molecular diversity of HIV-1, enabling the detection of emerging HIV-1 variants and improving the tracking of the epidemic worldwide. The rapid evolution of HIV within infected hosts contributes significantly to the elusiveness of this pathogen from host antiviral responses. The complex nature of HIV envelope glycoprotein that is inherently resistant to neutralization, the selective infection, progressive destruction and impaired regeneration of CD4+ T helper cells, generation of cytotoxic T lymphocyte (CTL) escape mutants, together with high genetic diversity with continually evolving HIV variants worldwide, makes design of an effective vaccine a formidable task. Given the rapidity and unpredictability with which HIV-1 genetic forms may propagate in future, a vaccine protective against all major HIV-1 circulating genetic forms is desirable, which could require multivalent formulations. Understanding the kinetics and directions of this continuing adaptation and its impact on viral fitness, immunogenicity and pathogenicity are crucial to the successful design of effective HIV vaccines. In this review, we focus on extensive diversity of HIV-1, emergence of recombinant forms and their impact on diagnosis, antiretroviral therapy, disease progression, transmission, and vaccine development.

AIDS Vaccines↗

PubMed2004

Polymorphism of Fc receptor IIa for immunoglobulin G is associated with placental malaria in HIV-1-positive women in western Kenya.

BACKGROUND: Genetic polymorphism of the Fc receptor IIa for immunoglobulin (Ig) G (Fc gamma RIIa) determines IgG subclass binding. Previous studies have shown that individuals with the IgG1/3-binding Fc gamma RIIa-Arg/Arg131 genotype are relatively protected against high-density malaria, whereas individuals with the IgG2-binding Fc gamma RIIa-His/His131 genotype are at increased risk for developing cerebral malaria. The present study was undertaken to examine the relationship between Fc gamma RIIa polymorphism and placental malaria (PM) in pregnant women of known human immunodeficiency virus (HIV)-1 status. METHODS: Fc gamma RIIa genotype was determined in 903 pregnant women who had participated in a study designed to assess the effect that PM has on vertical transmission of HIV-1. Fc gamma RIIa polymorphism was assessed in relation to PM. RESULTS: Among HIV-negative women, there was no difference in the distribution of the Fc gamma RIIa polymorphism by PM status. However, among HIV-positive women, the frequency of the Fc gamma RIIa-His/His131 genotype was significantly higher in women with PM than in women without PM (31% vs. 22%, respectively [P=.032]). In multivariate analysis, the adjusted odds ratio for PM in HIV-positive women with the Fc gamma RIIa-His/His131 genotype versus women in the Fc gamma RIIa-His/Arg131 reference group was 1.72 (95% confidence interval, 1.11-2.69 [P=.016]). CONCLUSIONS: The present study suggests that the IgG2-binding Fc gamma RIIa-His/His131 genotype is associated with enhanced susceptibility to PM in HIV-positive women but not in HIV-negative women.

Alleles↗

PubMed2004

Activity of alpha- and theta-defensins against primary isolates of HIV-1.

Theta-defensins are lectin-like, cyclic octadecapeptides found in the leukocytes of nonhuman primates. They are also homologues of the more familiar alpha-defensins expressed by humans and certain other mammals. This study compares the ability of six theta-defensins (hominid retrocyclins 1-3 and rhesus theta-defensins 1-3) and four human alpha-defensins (human neutrophil peptides (HNPs) 1-4) to bind gp120 and CD4. In addition, we compared the ability of these theta-defensins and HNP-1 to protect J53-BL cells (an indicator cell line) from primary HIV-1 isolates that varied in subtype and coreceptor usage. The most potent theta-defensin, retrocyclin-2, bound with exceptionally high affinity to gp120 (K(D), 9.4 nM) and CD4 (K(D), 6.87 nM), and its effectiveness against subtype B isolates (IC(50), 1.05 +/- 0.28 microg/ml; 520 +/- 139 nM) was approximately twice as great as that of HNP-1 on a molar basis. We also show, for the first time, that human alpha-defensins, HNPs 1-3, are lectins that bind with relatively high affinity to gp120 (K(D) range, 15.8-52.8 nM) and CD4 (K(D) range, 8.0-34.9 nM). Proteins found in human and FBS bound exogenous HNP-2 and retrocyclin-1, and competed with their ability to bind gp120. However, even the low concentrations of alpha-defensins found in normal human serum suffice to bind over half of the gp120 spikes on HIV-1 and a higher percentage of cell surface CD4 molecules. Although this report principally concerns the relationship between carbohydrate-binding and the antiviral properties of alpha- and theta-defensins, the lectin-like behavior of defensins may contribute to many other activities of these multifunctional peptides.

Amino Acid Sequence↗

PubMed2004

CCR5 promoter human haplogroups associated with HIV-1 disease progression in Thai injection drug users.

BACKGROUND: An evolutionary-based analysis of the CC chemokine receptor 5 gene (CCR5) promoter region has identified nine stable human haplogroups, within which certain haplogroups appear to influence HIV-1 disease progression differentially among Caucasians and African-Americans. OBJECTIVE: To assess the influence of CCR5 haplogroups on HIV-1 disease progression in a Thai population. DESIGN: Haplogroup analysis of HIV-1-seropositive injection drug users (IDU) participating in a prospective cohort study in Bangkok. All were documented seroconverters with a median follow-up time of 3.5 years (range, 0.2-7.0). METHODS: From a cohort of 130 IDU, 106 (81.5%) were genotyped for the CCR2b-64I, CCR5-delta32 and seven CCR5 promoter alleles constituting the CCR5 haplogroups. Survival curves and adjusted Cox proportional hazards models were used to assess the effect of haplogroups on the time from HIV-1 infection until CD4 count < 200 x 10(6) cells/l. RESULTS: The most common CCR5 haplogroups were HHC (61.8%), followed by HHE (15.6%) and HHF*2 (14.6%). HHE was associated with an accelerated CD4 count decline to < 200 x 10(6) cells/l (adjusted relative hazard, 1.88; 95% confidence interval, 1.05-3.36; P = 0.02). CONCLUSIONS: This is the first evidence that the CCR5 haplogroup E speeds the decline of the CD4 cell count and may lead to accelerated disease progression among HIV-infected Thais. These new observations highlight the need for additional studies involving populations in Asia.

Adult↗

PubMed2004

Polymorphism of Fc receptor IIa for IgG in infants is associated with susceptibility to perinatal HIV-1 infection.

OBJECTIVE: To evaluate the effect of polymorphism of the Fc gamma receptor IIa, which is associated with differential human IgG subclass binding, on perinatal HIV-1 transmission. METHODS: Fc gamma RIIa genotype was tested in 448 HIV-seropositive mothers and their infants from a cohort study designed to assess the effect of placental malaria on HIV vertical transmission conducted from 1996 to 2001 in western Kenya. Fc gamma RIIa polymorphism was analyzed for associations with susceptibility to perinatal HIV infection and all-cause child mortality in HIV-positive children. RESULTS: Overall, 20% of infants were perinatally infected with HIV. There was no statistically significant association between maternal genotype and perinatal HIV-1 transmission. However, frequency of the infant Fc gamma RIIa His/His131 genotype was higher in HIV-positive compared with HIV-negative infants (35% and 21%, respectively), whereas the distribution was reversed (15% and 28%, respectively) for infants with the Fc gamma RIIa Arg/Arg131 genotype. Multivariate logistic regression controlling for maternal and infant confounding factors demonstrated that the odds of perinatal HIV infection in infants with the Fc gamma RIIa His/His131 versus Fc gamma RIIa His/Arg131 genotypes were significantly higher (adjusted odds ratio, 2.22; 95% confidence interval, 1.23-4.02; P = 0.009). There was no evidence for an association between HIV-positive child all-cause mortality and Fc gamma RIIa genotype. CONCLUSIONS: This study provides the first evidence that the infant Fc gamma RIIa His/His131 genotype is associated with susceptibility to perinatal HIV-1 transmission and further suggests that there is a dose-response relationship for the effect of the Fc gamma RIIa His131 gene on transmission.

Adult↗

PubMed2004

Improved breadth and potency of an HIV-1-neutralizing human single-chain antibody by random mutagenesis and sequential antigen panning.

Several human monoclonal antibodies can neutralize a range of human immunodeficiency virus type 1 (HIV-1) primary isolates but their potency and related ability to suppress generation of HIV-1 escape mutants is significantly lower than the activity of antiretroviral drugs currently in clinical use. Recently, a human Fab, X5, was identified and found to neutralize primary isolates from different clades. Further improvement of the potency and breadth of HIV-1 neutralization by this antibody could be critical for its potential use in the treatment of HIV-1-infected patients. However, increasing potency of an antibody by selection from libraries may lead to a decrease in the breadth of neutralization. In an attempt to solve this problem, we subjected a random mutagenesis library of the scFv X5 to sequential rounds of selection on non-homologous HIV-1 envelope glycoproteins (Envs) dubbed sequential antigen panning (SAP). By using SAP, we identified two scFv antibodies, m6 and m9, that were tested with a panel of 33 diverse primary HIV-1 infectious isolates in an assay based on a reporter cell-line expressing high levels of CD4, CCR5 and CXCR4. The IC(50) was less than 50 microg/ml for 21 (m6) and 19 (m9) out of 29 isolates from group M (subtypes A-C, F, G and CRF-01AE) and one isolate from group N; three isolates from group O were not significantly inhibited at 50 microg/ml. The average IC(50) values for the two antibodies were significantly (p<0.001, n=29) lower compared to scFv X5. Their inhibitory activity does not appear to be related to the HIV-1 subtype, coreceptor usage or the disease stage. m9 inhibited infection of peripheral blood mononuclear cells by the primary isolates JRCSF, 89.6 and BR020 with IC(90) of 4, 6 and 25 microg/ml, respectively; for a single-round infection by pseudovirus, the IC(90) for JRSCF, 89.6, YU2 and HXBc2 was 15, 5, 15 and 5 microg/ml, respectively. In these two assays the IC(90) for m9 was, on average, two- to threefold lower than for scFv X5. These results demonstrate that both the potency and the breadth of HIV-1 neutralization of one of the few known potent broadly cross-reactive human monoclonal antibodies, scFv X5, could be improved significantly. However, only experiments in animal models and clinical trials in humans will show whether these new scFvs and the approach for their identification have potential in the development of prophylactics and therapeutics for HIV-1 infections.

Antibody Affinity↗

PubMed2004

Characterization of human immunodeficiency virus type-1 from HIV-1 seropositive cases with undetectable viremia.

BACKGROUND: Human immunodeficiency virus type 1 (HIV-1) viral load has become a standard of care among HIV-1-infected patients; however, a small number of patients have undetectable viral load even though they have never been treated. METHODS: By using RT-PCR and DNA-PCR, and followed by sequencing and phylogenetic analyses, a detailed molecular characterization was carried out from five HIV-1-seropositive patients who had undetectable viral load by commercially available ultrasensitive viral load assays. RESULTS: Of the four patients whose plasmas were available, viral RNAs were detected in three of them by using an in-house RT-PCR in at least one of the three regions (integrase, protease or envgp41). The fourth patient had positive RT-PCR signals in these regions only when RNA isolated from the supernatant of cocultivated patient PBLs with PHA-stimulated HIV-1 negative donor PBLs was used. Further analysis of DNA extracted from the PBMCs revealed that four of the five patients had detectable proviral sequences in at least two of the three regions. The fifth patient had only positive PCR results in all three regions when DNA isolated from PHA-stimulated patient's PBLs was used. Phylogenetic analysis of protease and envgp41 regions revealed that three patients were infected with subtype B viruses while the remaining two patients were infected with subtype C and CRF02_AG viruses. These subtypes coincided with geographic origin and known molecular epidemiology of HIV-1 infection. CONCLUSION: These data provide evidence that both subtype B and non-B HIV-1 infection can result in undetectable viral load in HIV-1-infected patients and that efforts should continue to further characterize these viruses.

Adult↗

PubMed2004

Genetic diversity and high proportion of intersubtype recombinants among HIV type 1-infected pregnant women in Kisumu, western Kenya.

The high genetic diversity of HIV-1 continues to complicate effective vaccine development. To better understand the extent of genetic diversity, intersubtype recombinants and their relative contribution to the HIV epidemic in Kenya, we undertook a detailed molecular epidemiological investigation on HIV-1-infected women attending an antenatal clinic in Kisumu, Kenya. Analysis of gag-p24 region from 460 specimens indicated that 310 (67.4%) were A, 94 (20.4%) were D, 28 (6.1%) were C, 9 (2.0%) were A2, 8 (1.7%) were G, and 11 (2.4%) were unclassifiable. Analysis of the env -gp41 region revealed that 326 (70.9%) were A, 85 (18.5%) D, 26 (5.7%) C, 9 (2.0%) each of A2 and G, 4(0.9%) unclassifiable, and 1 (0.2%) CRF02_AG. Parallel analyses of the gag-p24 and env-gp41 regions indicated that 344 (74.8%) were concordant subtypes, while the remaining 116 (25.2%) were discordant subtypes. The most common discordant subtypes were D/A (40, 8.7%), A/D (27, 5.9%), C/A (11, 2.4%), and A/C (8, 1.7%). Further analysis of a 2.1-kb fragment spanning the gag-pol region from 38 selected specimens revealed that 19 were intersubtype recombinants and majority of them were unique recombinant forms. Distribution of concordant and discordant subtypes remained fairly stable over the 4-year period (1996-2000) studied. Comparison of amino acid sequences of gag-p24 and env-gp41 regions with the subtype A consensus sequence or Kenyan candidate vaccine antigen (HIVA) revealed minor variations in the immunodominant epitopes. These data provide further evidence of high genetic diversity, with subtype A as the predominant subtype and a high proportion of intersubtype recombinants in Kenya.

AIDS Serodiagnosis↗

PubMed2004

RC-101, a retrocyclin-1 analogue with enhanced activity against primary HIV type 1 isolates.

Rhesus macaques express three theta-defensins (RTDs 1-3), cyclic octadecapeptides with antiviral and lectin-like properties. Corresponding theta-defensin genes exist and are expressed in humans, but a signal sequence mutation prevents the formation of mature theta-defensin peptides. Retrocyclin-1 is a theta-defensin peptide whose precursor is encoded by human theta-defensin pseudogenes. It can protect human peripheral blood lymphocytes from infection by R5 and X4 strains of HIV-1, and provides a molecular template for designing novel antiviral agents. In this study, we used JC53-BL reporter cells to assess the activity of retrocyclin-1 (RC-100) and several analogues against primary HIV-1 isolates, including R5 and R5X4 strains of subtypes A-D, CRF-01_AE, and recombinants. Each analogue differed from retrocyclin-1 by a single amino acid substitution: Gly --> Tyr in RC-106, RC-115, and RC-116, and Arg --> Lys in RC-101. Although the modification in RC-101 was chemically conservative, this peptide was significantly more potent than retrocyclin-1 across the panel of primary isolates. We performed surface plasmon resonance binding studies, using recombinant gp120 and CD4 produced in insect cells. Although RC-100 and RC-101 bound gp120 LAV/IIIB with a K(d) of 30-35 nM, they bound gp120 from CRF-01_AE strains (CM 235 and 93TH975.15) with K(d) values of 200-750 nM. Overall, our findings suggest that clade-related differences in gp120 glycosylation impact the ability of retrocyclin-1 to bind this viral glycoprotein, and modulate the peptides' ability to prevent HIV-1 infection. The performance of RC-101 suggests that additional "engineering" could further enhance the antiviral properties of theta-defensins.

Cell Line↗

PubMed2004

Maternal malaria and perinatal HIV transmission, western Kenya.

To determine whether maternal placental malaria is associated with an increased risk for perinatal mother-to-child HIV transmission (MTCT), we studied HIV-positive women in western Kenya. We enrolled 512 mother-infant pairs; 128 (25.0%) women had placental malaria, and 102 (19.9%) infants acquired HIV perinatally. Log10 HIV viral load and episiotomy or perineal tear were associated with increased perinatal HIV transmission, whereas low-density placental malaria (<10,000 parasites/mL) was associated with reduced risk (adjusted relative risk [ARR] 0.4). Among women dually infected with malaria and HIV, high-density placental malaria (>10,000 parasites/mL) was associated with increased risk for perinatal MTCT (ARR 2.0), compared to low-density malaria. The interaction between placental malaria and MTCT appears to be variable and complex: placental malaria that is controlled at low density may cause an increase in broad-based immune responses that protect against MTCT; uncontrolled, high-density malaria may simultaneously disrupt placental architecture and generate substantial antigen stimulus to HIV replication and increase risk for MTCT.

Female↗

PubMed2003

Genetic diversity of HIV-1 in western Kenya: subtype-specific differences in mother-to-child transmission.

BACKGROUND: Little is known about the impact of HIV-1 group M subtypes on mother-to-child transmission (MTCT) of HIV-1 in African settings where multiple HIV-1 group M subtypes are co-circulating. OBJECTIVE: To assess the role of subtype variation on MTCT. METHODS: HIV-1-infected women attending an antenatal clinic in western Kenya were enrolled for a prospective study (1996-2000) of MTCT. HIV-1 subtype analysis of p24gag and gp41env identified potential recombinants, and their role in MTCT was determined. RESULTS: Among 414 women for whom HIV-1 subtype and HIV transmission status were available, MTCT occurred in 80 (19.3%). MTCT rates were higher among women with subtype D compared with subtype A in either the gp41 region [31.6 versus 16.1%, relative risk (RR) 2.0, P=0.002] or p24 region (29.9 versus 18.0%, RR 1.7, P=0.02). Discordant subtype combinations were identified in 103 of the women (25.9%), and were associated with higher rates of MTCT (28.2 versus 17.0%, RR 1.7, P=0.01). In multivariate analysis, women with subtype combinations D/D, D/A, and A/D had an increased risk of MTCT (adjusted odds ratios 3.5, 2.5, 6.2; P=0.005, 0.05, and 0.0003, respectively) compared with A/A women after adjustment for maternal HIV viral load, placental malaria infection, episiotomy or perineal tear, and low birthweight. CONCLUSION: MTCT appears to be more common among mothers infected with subtype D compared with subtype A. Such differences in MTCT frequency may be caused by altered cellular tropism for placental cell types.

Female↗

PubMed2003

Polymorphisms in the CCR5 coding and noncoding regions among HIV type 1-exposed, persistently seronegative female sex-workers from Thailand.

Resistance to HIV-1 infection despite repeated exposures has been associated with one or more HIV-specific responses, enhanced nonspecific immune modifications, and/or host genetic polymorphisms in certain individuals (highly exposed, persistently seronegative, HEPS). In the present investigation, we focused on the CCR5 gene polymorphisms and the association of such mutations to resistance to HIV-1 infection among 12 HEPS women in Chiang Rai, northern Thailand, and compared our findings with data from 10 HIV-1-infected and 9 HIV-1-uninfected unexposed women from the same geographic area. Although we have previously shown that none of the Thai women carried the Delta32 mutation, further analysis of the CCR5 coding gene region revealed that none of the women had other mutations that affect coreceptor activity (C101X or FS299) or chemokine responses (C20S, A29S, L55Q, C178R). Analysis of the CCR5 promoter region revealed that the CCR5 haplogroup C (HHC; 60%) was the predominant haplogroup among these women. Comparative analysis of the frequencies of different haplogroups among the three groups did not reveal any statistically significant differences (p > 0.05). However, we did find that two individuals from the HEPS group were homozygous for HHF*2 (the CCR2b- 64I bearing haplogroup) compared to none from the HIV-1-infected and -uninfected groups. There was no detectable difference in specific CCR5 haplogroups and their ability to mediate env fusion or to mediate HIV-1 infection in vitro. These data suggest that homozygosity of the HHF*2 haplogroup may be one of the factors that mediate resistance to HIV-1 infection in this cohort of HEPS women.

Adult↗

PubMed2003

Detection of human T-lymphotropic virus (HTLV) tax sequences in New York City blood donors seronegative for HTLV types 1 and 2.

A potential public health concern is the reported detection of the human T-lymphotropic virus (HTLV) tax gene in the lymphocytes of up to 11% of a low-risk group of New York City blood donors (NYBD). This study aimed to independently confirm the prevalence of HTLV tax sequences in 293 NYBD. All NYBD tested negative for antibodies to HTLV types 1 and 2 and HTLV Tax. HTLV tax sequences were not detected in the NYBD lymphocytes. These data demonstrate the lack of HTLV-1 tax in this group of NYBD at low risk for HTLV infection.

Adult↗