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R Kaslow

Publications and source records attributed to R Kaslow.

At least 19 recordsLinked to original sources
PubMed2001

Effect of a single amino acid change in MHC class I molecules on the rate of progression to AIDS.

BACKGROUND: From studies of genetic polymorphisms and the rate of progression from human immunodeficiency virus type 1 (HIV-1) infection to the acquired immunodeficiency syndrome (AIDS), it appears that the strongest susceptibility is conferred by the major-histocompatibility-complex (MHC) class I type HLA-B*35,Cw*04 allele. However, cytotoxic T-lymphocyte responses have been observed against HIV-1 epitopes presented by HLA-B*3501, the most common HLA-B*35 subtype. We examined subtypes of HLA-B*35 in five cohorts and analyzed the relation of structural differences between HLA-B*35 subtypes to the risk of progression to AIDS. METHODS: Genotyping of HLA class I loci was performed for 850 patients who seroconverted and had known dates of HIV-1 infection. Survival analyses with respect to the rate of progression to AIDS were performed to identify the effects of closely related HLA-B*35 subtypes with different peptide-binding specificities. RESULTS: HLA-B*35 subtypes were divided into two groups according to peptide-binding specificity: the HLA-B*35-PY group, which consists primarily of HLA-B*3501 and binds epitopes with proline in position 2 and tyrosine in position 9; and the more broadly reactive HLA-B*35-Px group, which also binds epitopes with proline in position 2 but can bind several different amino acids (not including tyrosine) in position 9. The influence of HLA-B*35 in accelerating progression to AIDS was completely attributable to HLA-B*35-Px alleles, some of which differ from HLA-B*35-PY alleles by only one amino acid residue. CONCLUSIONS: This analysis shows that, in patients with HIV-1 infection, a single amino acid change in HLA molecules has a substantial effect on the rate of progression to AIDS. The different consequences of HLA-B*35-PY and HLA-B*35-Px in terms of disease progression highlight the importance of the epitope specificities of closely related class I molecules in the immune defense against HIV-1.

Acquired Immunodeficiency Syndrome↗
PubMed2000

Causal pathways for CCR5 genotype and HIV progression.

A homozygous 32-bp deletion in the gene encoding CCR5, a major coreceptor for HIV-1, leads to resistance to infection with HIV-1, and heterozygosity for the deletion is associated with delayed disease progression in persons infected with HIV-1. We investigated the effect of CCR5 heterozygosity on disease progression as measured by both CD4+ T-cell count decline and the occurrence of clinical AIDS symptoms. Using a unified statistical model for CD4 count progression and AIDS development, we examined whether the effect of CCR5 heterozygosity on clinical AIDS is direct or indirect through its effect on CD4 counts. Based on data from the Multicenter AIDS Cohort Study, we noted a protective effect of CCR5 heterozygosity on both CD4 cell count progression and on AIDS occurrence. Furthermore, we found that this protective effect on the occurrence of AIDS was completely mediated through an effect on the CD4 marker. Additional adjustment for the effect of an initial viral load measurement indicate that CCR5 heterozygosity did not have predictive value for either CD4 progression or the development of AIDS beyond its association with early viral load.

Adult↗
PubMed1999

Correlation between circulating stromal cell-derived factor 1 levels and CD4+ cell count in human immunodeficiency virus type 1-infected individuals.

Stromal cell-derived factor 1 (SDF-1) is the natural ligand that recognizes CXCR4, which also serves as a coreceptor for some strains of HIV-1. In this study, we explored SDF-1 blood levels among HIV-1-infected individuals exhibiting a wide range of CD4+ cell counts. Plasma or serum concentrations of SDF-1 protein were measured by ELISA in samples from 31 HIV-1-seronegative individuals and 79 HIV-1-infected subjects. Although SDF-1 protein levels were stable for months among seronegative individuals (mean intrasubject variation, 17%), the absolute values varied widely (0.28 to 106.5 ng/ml; mean, 25.6 ng/ml). In HIV-1-infected subjects, there was a direct correlation between SDF-1 level and CD4+ cell count. Subjects with fewer than 50 CD4+ cells per cubic microliter of blood had significantly lower mean SDF-1 levels (+/-SD) than did either HIV-1-infected subjects with higher CD4+ cell counts or uninfected controls: CD4+ cell count <50, mean SDF-1 level of 10.7+/-33.7, 50 < CD4+ cell count <200, mean SDF-1 level of 12.9+/-19.0, 200 < CD4+ cell count <500, mean SDF-1 level of 19.3+/-36.8; CD4+ cell count >500, mean SDF-1 level of 18.5+/-25.2; uninfected control mean SDF-1 level, 25.6+/-34.7. No significant change in SDF-1 level was detected after administration of antiretroviral therapy in nine subjects with advanced disease (mean intrasubject variation, 43%). Analysis of SDF-1 mRNA expression in lymph nodes from HIV-1-infected subjects at different disease stages revealed that the medullary cords contained stromal cells that express SDF-1 mRNA. This preliminary analysis suggests a possible link between lower SDF-1 levels and disease progression.

Adult↗
PubMed1999

HLA and HIV-1: heterozygote advantage and B*35-Cw*04 disadvantage.

A selective advantage against infectious disease associated with increased heterozygosity at the human major histocompatibility complex [human leukocyte antigen (HLA) class I and class II] is believed to play a major role in maintaining the extraordinary allelic diversity of these genes. Maximum HLA heterozygosity of class I loci (A, B, and C) delayed acquired immunodeficiency syndrome (AIDS) onset among patients infected with human immunodeficiency virus-type 1 (HIV-1), whereas individuals who were homozygous for one or more loci progressed rapidly to AIDS and death. The HLA class I alleles B*35 and Cw*04 were consistently associated with rapid development of AIDS-defining conditions in Caucasians. The extended survival of 28 to 40 percent of HIV-1-infected Caucasian patients who avoided AIDS for ten or more years can be attributed to their being fully heterozygous at HLA class I loci, to their lacking the AIDS-associated alleles B*35 and Cw*04, or to both.

Acquired Immunodeficiency Syndrome↗
PubMed1997

Frequency of HLA allele-specific peptide motifs in HIV-1 proteins correlates with the allele's association with relative rates of disease progression after HIV-1 infection.

An HLA allele-specific cytotoxic T lymphocyte response is thought to influence the rate of disease progression in HIV-1-infected individuals. In a prior study of 139 HIV-1-infected homosexual men, we identified HLA class I alleles and observed an association of specific alleles with different relative hazards for progression to AIDS. Seeking an explanation for this association, we searched HIV-1 protein sequences to determine the number of peptides matching motifs defined by combinations of specific amino acids reported to bind 16 class I alleles. Analyzing complete sequences of 12 clade B HIV isolates, we determined the number of allele motifs that were conserved (occurring in all 12 isolates) and nonconserved (occurring in only one isolate), as well as the average number of allele motifs per isolate. We found significant correlations with an allele's association with disease progression for counts of conserved motifs in gag (R = 0.73; P = 0.002), pol (R = 0.58, P = 0.024), gp120 (R = 0.78, P = 0.00056), and total viral protein sequences (R = 0.67, P = 0.0058) and also for counts of nonconserved motifs in gag (R = 0.62, P = 0.013), pol (R = 0.74, P = 0.0017), gp41 (R = 0.52, P = 0.046), and total viral protein (R = 0.71, P = 0.0033). We also found significant correlations for the average number of motifs per isolate for gag, pol, gp120, and total viral protein. This study provides a plausible functional explanation for the observed association of different HLA alleles with variable rates of disease progression.

Alleles↗
PubMed1997

Contrasting genetic influence of CCR2 and CCR5 variants on HIV-1 infection and disease progression. Hemophilia Growth and Development Study (HGDS), Multicenter AIDS Cohort Study (MACS), Multicenter Hemophilia Cohort Study (MHCS), San Francisco City Cohort (SFCC), ALIVE Study.

The critical role of chemokine receptors (CCR5 and CXCR4) in human immunodeficiency virus-type 1 (HIV-1) infection and pathogenesis prompted a search for polymorphisms in other chemokine receptor genes that mediate HIV-1 disease progression. A mutation (CCR2-64I) within the first transmembrane region of the CCR2 chemokine and HIV-1 receptor gene is described that occurred at an allele frequency of 10 to 15 percent among Caucasians and African Americans. Genetic association analysis of five acquired immunodeficiency syndrome (AIDS) cohorts (3003 patients) revealed that although CCR2-64I exerts no influence on the incidence of HIV-1 infection, HIV-1-infected individuals carrying the CCR2-64I allele progressed to AIDS 2 to 4 years later than individuals homozygous for the common allele. Because CCR2-64I occurs invariably on a CCR5-+-bearing chromosomal haplotype, the independent effects of CCR5-Delta32 (which also delays AIDS onset) and CCR2-64I were determined. An estimated 38 to 45 percent of AIDS patients whose disease progresses rapidly (less than 3 years until onset of AIDS symptoms after HIV-1 exposure) can be attributed to their CCR2-+/+ or CCR5-+/+ genotype, whereas the survival of 28 to 29 percent of long-term survivors, who avoid AIDS for 16 years or more, can be explained by a mutant genotype for CCR2 or CCR5.

Acquired Immunodeficiency Syndrome↗
PubMed1997

Characteristics of inner-city children with asthma: the National Cooperative Inner-City Asthma Study.

Asthma morbidity has increased dramatically in the past decade, especially among poor and minority children in the inner cities. The National Cooperative Inner-City Asthma Study (NCICAS) is a multicenter study designed to determine factors that contribute to asthma morbidity in children in the inner cities. A total of 1,528 children with asthma, ages 4 to 9 years old, were enrolled in a broad-based epidemiologic investigation of factors which were thought to be related to asthma morbidity. Baseline assessment included morbidity, allergy evaluation, adherence and access to care, home visits, and pulmonary function. Interval assessments were conducted at 3, 6, and 9 months after the baseline evaluations. Over the one-year period, 83% of the children had no hospitalizations and 3.6% had two or more. The children averaged 3 to 3.5 days of wheeze for each of the four two-week recall periods. The pattern of skin test sensitivity differed from other populations in that positive reactions to cockroach were higher (35%) and positive reactions to house dust mite were lower (31%). Caretakers reported smoking in 39% of households of children with asthma, and cotinine/creatinine ratios exceeded 30 ng/mg in 48% of the sample. High exposure (> 40 ppb) to nitrogen dioxide was found in 24% of homes. Although the majority of children had insurance coverage, 53% of study participants found it difficult to get follow-up asthma care. The data demonstrate that symptoms are frequent but do not result in hospitalization in the majority of children. These data indicate a number of areas which are potential contributors to the asthma morbidity in this population, such as environmental factors, lack of access to care, and adherence to treatment. Interventions to reduce asthma morbidity are more likely to be successful if they address the many different asthma risks found in the inner cities.

Allergens↗
PubMed1997

Detection of infection with human immunodeficiency virus type 1 before seroconversion: correlation with clinical symptoms and outcome.

Early (pre-seroconversion) infection with human immunodeficiency virus type 1 (HIV-1) was identified in 50 of 267 participants in the Multicenter AIDS Cohort Study. These 50 men had a positive EIA result, which detected IgM antibody (n = 35), p24 antigen, or serum HIV RNA (n = 15) at their last "seronegative" visit. At that visit, the mean CD4 lymphocyte number (890/mm3 vs. 1038/mm3) was significantly lower than in men who subsequently seroconverted but had no evidence of early infection. The decline in CD4 cells was slower and the duration of AIDS-free time longer in the 19 men who were symptomatic in comparison to the 31 asymptomatic men with early infection, but differences were not significant.

Acquired Immunodeficiency Syndrome↗
PubMed1996

Genetic restriction of HIV-1 infection and progression to AIDS by a deletion allele of the CKR5 structural gene. Hemophilia Growth and Development Study, Multicenter AIDS Cohort Study, Multicenter Hemophilia Cohort Study, San Francisco City Cohort, ALIVE Study.

The chemokine receptor 5 (CKR5) protein serves as a secondary receptor on CD4(+) T lymphocytes for certain strains of human immunodeficiency virus-type 1 (HIV-1). The CKR5 structural gene was mapped to human chromosome 3p21, and a 32-base pair deletion allele (CKR5Delta32) was identified that is present at a frequency of approximately0.10 in the Caucasian population of the United States. An examination of 1955 patients included among six well-characterized acquired immunodeficiency syndrome (AIDS) cohort studies revealed that 17 deletion homozygotes occurred exclusively among 612 exposed HIV-1 antibody-negative individuals (2.8 percent) and not at all in 1343 HIV-1-infected individuals. The frequency of CKR5 deletion heterozygotes was significantly elevated in groups of individuals that had survived HIV-1 infection for more than 10 years, and, in some risk groups, twice as frequent as their occurrence in rapid progressors to AIDS. Survival analysis clearly shows that disease progression is slower in CKR5 deletion heterozygotes than in individuals homozygous for the normal CKR5 gene. The CKR5Delta32 deletion may act as a recessive restriction gene against HIV-1 infection and may exert a dominant phenotype of delaying progression to AIDS among infected individuals.

Acquired Immunodeficiency Syndrome↗
PubMed1993

Composite risk score for Kaposi's sarcoma based on a case-control and longitudinal study in the Multicenter AIDS Cohort Study (MACS) population.

The possibility that an agent in addition to human immunodeficiency virus type 1 may be involved in the etiology of Kaposi's sarcoma in acquired immunodeficiency syndrome (AIDS) patients was investigated between 1984 and 1992 in this nested case-control analysis from the Multicenter AIDS Cohort Study (MACS) of homosexual and bisexual men. A total of 316 cases of Kaposi's sarcoma were identified and compared with 510 participants with AIDS and no evidence of cancer. More of the Kaposi's sarcoma cases were from Los Angeles and used a higher number of recreational drugs. The Kaposi's sarcoma cases were also more active sexually. There was a dose-response relation between Kaposi's sarcoma and the number of sexual partners, with an odds ratio of 2 between the most and least sexually active subgroups. The odds ratio for Kaposi's sarcoma increased to 4.18 (95% confidence interval 1.29-14.1) in the presence of a history of five infections. Hepatitis and gonorrhea contributed the most to this relation. The various observed odds ratios did not change after multivariate adjustment for the other risk factors. A model was developed combining all predictive associations into a composite risk score ranging from one to 12 and based on history of infections, sexual activity, use of poppers/nitrites, and having had sexual partners from the West Coast of the United States. The subgroup with the highest scores, compared to the subgroup with the lowest score, had an odds ratio of 8.93 (95% confidence interval 3.21-30.44) for Kaposi's sarcoma. A longitudinal proportional hazards analysis among all 2,190 human immunodeficiency virus type 1-seroprevalent men at study entry, based on this risk score and CD4 cells at baseline, confirmed these findings. Identifying these specific subgroups that are at high and low risk for Kaposi's sarcoma will help future investigations to be more focused in their search for an additional etiologic factor for Kaposi's sarcoma in AIDS.

Acquired Immunodeficiency Syndrome↗
PubMed1993

Relationship of hepatitis B virus infection to human immunodeficiency virus type 1 infection.

The Multicenter AIDS Cohort Study (MACS) was designed to study the natural history of human immunodeficiency virus type 1 (HIV-1) infection, including the relationship between hepatitis B virus (HBV) and HIV-1 infection. In total, 4954 homosexual men were recruited from April 1984 through March 1985 and have been followed up thereafter every 6 months. Hepatitis B surface antigen and hepatitis B core antibody were tested for at the first visit by RIA or EIA; HIV-1 antibody testing was done at each visit by ELISA and confirmed by Western blot assay. The role of HBV infection in HIV-1 seroconversion was studied by stratification for sexual behavior and disease visit by visit. The adjusted risk ratio was 2.02 for hepatitis B surface antigen carriers and 2.14 for hepatitis-immune cases compared with hepatitis B-susceptible subjects. Similar results were obtained using a logistic regression model. After taking into account changes in sexual behavior and disease over time, the authors conclude that past HBV infection remains suspect as a cofactor or as a surrogate for other factors associated with HIV-1 seroconversion.

Blotting, Western↗
PubMed1992

Influence of HIV-1 infection and cigarette smoking on leukocyte profiles in homosexual men. The Multicenter AIDS Cohort Study.

The interaction between the effects of HIV-1 infection and cigarette smoking on leukocyte profiles was studied in 307 HIV-1 seroconverters in the Multicenter AIDS Cohort Study (MACS). Longitudinal data for white blood cell (WBC) counts, WBC differentials, T cell subsets, and smoking behavior were collected semiannually for up to 7 years. Prior to seroconversion, total WBC count increased in direct proportion to daily cigarette consumption, but this effect disappeared within 3 years of seroconversion. Analyses of WBC subsets (lymphocytes, monocytes, and granulocytes) and lymphocyte subsets (CD4+, CD8+ and non-T[CD3-]) showed that smoking had only minor effects on the proportions of these cells. In contrast, HIV-1 seroconversion was associated with a dramatic decrease in CD4+ lymphocyte percentage, a large increase in CD8+ lymphocyte percentage, a small increase in total lymphocyte percentage, and small decreases in the non-T lymphocyte and granulocyte percentages. These findings indicate that the effect of smoking on CD4 cell counts is (a) nonspecific, (b) maximal in seronegative individuals; and (c) lost by 3 years after seroconversion. Although the mechanism of the loss of smoking-induced leukocytosis after seroconversion remains to be determined, our results suggest that the effects of smoking are not likely to be important in the clinical use of leukocyte measurements, including measurements of CD4 lymphocytes, in individuals who have been HIV-1 seropositive for more than 3 years.

CD4-CD8 Ratio↗
PubMed1992

The significance of western blot assays indeterminate for antibody to HIV in a cohort of homosexual/bisexual men. The Multicenter AIDS Cohort Study.

The objective of this study was to determine the frequency and significance of nondiagnostic Western blot (WB) assays in homosexual/bisexual men at risk of infection with HIV-1. The presence of a positive enzyme-linked antibody assay (EIA) confirmed by a positive WB was used as evidence of infection and seroconversion. Indeterminate WB assays were defined as reactions to only one viral gene product of HIV-1. Three analyses were conducted to (a) determine the frequency of such reactions in men who, during a 4-year period, did not develop diagnostic serologic reactions; (b) determine, retrospectively, the preseroconversion frequency of indeterminate WB assays in 286 men who seroconverted; and (c) evaluate in vitro production of specific antibody by peripheral blood mononuclear cells (PBMCs) as a method of indicating whether or not an indeterminate WB assay represents HIV-1 infection. Reactions to products of gag, pol, or env were noted in 8.0, 4.0, and 6.7% of 1,595 first-visit tests of men who remained seronegative for 4 years. Indeterminate reactions occurred in 204 men with negative EIAs who subsequently seroconverted and in 82 men with positive EIAs preconversion. Supernatants harvested from PBMCs of 2 of 36 seroconverters obtained one or two visits preseroconversion and cultured with pokeweed mitogen were antibody-positive. All were positive at the visit, with diagnostic serology. None of the supernatants from cells of 19 men with EIA-negative WB-indeterminate serologic assays were antibody-positive. Our results suggest that persistently EIA-negative homosexual/bisexual men who have indeterminate WB assays are unlikely to be infected with HIV-1.(ABSTRACT TRUNCATED AT 250 WORDS)

Bisexuality↗
PubMed1991

Cytomegalovirus IgG and IgA serum antibodies in a study of HIV infection and HIV related diseases in homosexual men.

The significance of serum IgG and IgA antibodies to cytomegalovirus (CMV) at various stages of human immune deficiency virus (HIV) infection was studied in 175 homosexual men. Sera were obtained from 123 HIV seropositives [41 asymptomatic, 29 with lymphadenopathy associated syndrome (LAS), 22 with AIDS related complex (ARC), and 31 AIDS patients], 17 HIV seroconverters, and 35 HIV asymptomatic seronegatives. The sera were tested blindly for CMV IgA and IgG antibodies using the immunoperoxidase assay (IPA) and CMV infected human embryo cells. Cross-sectional analysis of CMV IgG antibodies at a titer of greater than or equal to 20 showed 87% and 100% prevalence in the HIV seronegative groups and in the HIV seropositive groups, respectively (P less than 0.05). CMV IgG antibodies at a titer of greater than or equal to 80 were present in significantly higher proportions among the HIV seropositive subjects of the various groups as compared with the HIV seronegative homosexual men. However, in the HIV seronegatives who later seroconverted to HIV, a significantly higher prevalence of CMV antibodies (35%) was detected before HIV seroconversion, as compared with the persistently HIV seronegative subjects (14.3%) (P less than 0.05). The HIV seronegatives pre-HIV seroconversion also exhibited a significantly higher geometric mean titer (GMT) of CMV IgG antibodies (62.17 +/- 0.64) as compared with the persistently HIV seronegatives (34.0 +/- 0.6) (P = 0.03). Significantly higher GMTs of CMV IgG antibodies were detected in all the HIV seropositive groups as compared with the persistently HIV seronegative group. CMV IgG antibodies were not detected in the HIV seronegative subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

Epidemiologic patterns of upper respiratory illness and Pneumocystis carinii pneumonia in homosexual men.

The relationship between self-reported upper respiratory illness symptoms (URI) and human immunodeficiency virus Type 1 (HIV-1) was examined in homosexual men using semiannual visits from 1984 to 1988. Temporal and geographic patterns of Pneumocystis carinii pneumonia (PCP) diagnosis in these men during the same time period are also described. URI, including acute sinusitis, was reported more often by 916 HIV-1-seropositive participants than by 2,161 seronegative participants (32.21 versus 28.86% p less than 0.001). For 387 seropositive subjects who progressed to acquired immunodeficiency syndrome (AIDS), the proportion reporting URI peaked one visit pre-AIDS at a level significantly higher than matched control subjects (0.45 versus 0.28, p less than or equal to 0.001). The peak was higher for those with PCP as an initial diagnosis. Reported URI peaked in winter and troughed in summer, and PCP diagnosis rates peaked and troughed 4 months later, respectively. Cities with the highest reported rates of URI also had the highest proportions of AIDS cases with PCP as an initial diagnosis. No temporal or geographic patterns were observed for other HIV-1-related symptoms or non-PCP AIDS diagnoses. These patterns suggest the possibility of a person-to-person transmission of P. carinii similar to that of other respiratory pathogens, which would imply a need to consider stricter methods to prevent nosocomial transmission of this pathogen in inpatient and outpatient settings. Further investigation of these issues is needed.

Acquired Immunodeficiency Syndrome↗