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Biomedical subjects

Donald E Mosier

Publications and source records attributed to Donald E Mosier.

9 recordsLinked to original sources
PubMed2007

Evolution of CXCR4-using human immunodeficiency virus type 1 SF162 is associated with two unique envelope mutations.

CCR5-using human immunodeficiency virus type 1 (HIV-1) isolates typically gain CXCR4 use via multiple mutations in V3 and often V1/V2 regions of envelope, and patterns of mutations are distinct for each isolate. Here, we report that multiple CXCR4-using variants of a parental CCR5-using HIV-1 isolate, SF162, obtained by either target cell selection or CCR5 inhibition have a common mutation pattern characterized by the same two V3 mutations and that these mutations preexisted in some of the SF162 stocks. These results imply that SF162 has a single pathway for acquiring CXCR4 use and that prolonged culture is sufficient to select for R5X4 variants.

Cells, Cultured↗
PubMed2006

High prevalence of infection with a single hepatitis C virus genotype in a small rural community of Argentina.

BACKGROUND: During the years preceding this study, we noticed a relatively unusual high number of individuals with elevated alanine aminotransferase (ALT) levels in O'Brien, a small rural town in Argentina. Moreover, four individuals from this town underwent liver transplantation owing to hepatitis C virus (HCV)-induced liver cirrhosis. These findings prompted us to conduct a large population-based survey to evaluate the prevalence of HCV in this community. METHODS AND RESULTS: A total of 1637 individuals were studied. The overall HCV-seroprevalence was 5.7% (93/1637), being slightly higher in men (45/769; 5.9%) than in women (48/868; 5.5%). HCV seroprevalence increased with age, reaching a peak rate of 23.9% among individuals between 61 and 70 years of age. HCV RNA was present in 82.7% of all HCV seropositive individuals identified and 100% of them were infected with genotype 1b. ALT elevations were detected in 44% of HCV+ patients and were only observed among viremic individuals. Hepatitis B virus infection was also prevalent (52%) among HCV-seropositive patients. The most common risk factor associated with HCV transmission identified was the apparent use of inadequately sterilized glass syringes by a health care provider serving the community; however, other risk factors may have also played a role in the dissemination of HCV. CONCLUSIONS: Our findings provide an explanation for the relative high number of individuals with elevated ALT levels observed in this community and form the basis of future prospective studies on the natural history of genotype 1b infection.

Adolescent↗
PubMed2004

Prevention of vaginal SHIV transmission in rhesus macaques through inhibition of CCR5.

Topical agents, such as microbicides, that can protect against human immunodeficiency virus (HIV) transmission are urgently needed. Using a chimeric simian/human immunodeficiency virus (SHIV SF162), which is tropic for the chemokine receptor CCR5, we report that topical application of high doses of PSC-RANTES, an amino terminus-modified analog of the chemokine RANTES, provided potent protection against vaginal challenge in rhesus macaques. These experimental findings have potentially important implications for understanding vaginal transmission of HIV and the design of strategies for its prevention.

Administration, Intravaginal↗
PubMed2004

Evolutionary genetics: CCR5 mutation and plague protection.

A recent and prevalent mutation in the chemokine receptor CCR5 in humans of northern European ancestry has been proposed to provide protection against bubonic plague. Here we infect both normal and CCR5-deficient mice with the bacterium Yersinia pestis, the cause of the plague epidemics that wiped out one-third of Europeans in the Middle Ages, and find no difference in either bacterial growth or survival time between the two groups. Unless the pathogenesis of Yersinia infection differs markedly between mice and humans, our results indicate that CCR5 deficiency in people is unlikely to protect against plague.

Animals↗
PubMed2004

Intrinsic obstacles to human immunodeficiency virus type 1 coreceptor switching.

The natural evolution of human immunodeficiency virus type 1 infection often includes a switch in coreceptor preference late in infection from CCR5 to CXCR4, a change associated with expanded target cell range and worsened clinical prognosis. Why coreceptor switching takes so long is puzzling, since it requires as few as one to two mutations. Here we report three obstacles that impede the CCR5-to-CXCR4 switch. Coreceptor switch variants were selected by target cell replacement in vitro. Most switch variants showed diminished replication compared to their parental R5 isolate. Transitional intermediates were more sensitive to both CCR5 and CXCR4 inhibitors than either the parental R5 virus or the final R5X4 (or rare X4) variant. The small number of mutations in viruses selected for CXCR4 use were distinctly nonrandom, with a dominance of charged amino acid substitutions encoded by G-to-A transitions, changes in N-linked glycosylation sites, and isolate-specific mutation patterns. Diminished replication fitness, less-efficient coreceptor use, and unique mutational pathways may explain the long delay from primary infection until the emergence of CXCR4-using viruses.

Amino Acid Sequence↗
PubMed2003

CCR5 promoter polymorphism determines macrophage CCR5 density and magnitude of HIV-1 propagation in vitro.

The common CCR5 promoter polymorphism at position -2459 (A/G) has been associated with differences in the rate of progression to AIDS, where HIV-1-infected individuals with the CCR5 -2459 G/G genotype exhibit slower disease progression than those with the A/A genotype. Mechanisms underlying the relationship between these polymorphisms and disease progression are not known. Here through in vitro infection of peripheral blood mononuclear cells obtained from healthy Caucasian blood donors with macrophage-tropic HIV-1 isolates we observed low, medium, and high viral propagation in association with G/G, A/G, and A/A promoter genotypes, respectively. Flow cytometric analysis of unstimulated CD14+ monocytes from these same donors revealed a similar hierarchy of CCR5 receptor density in association with promoter genotypes. Finally, PBMC from persons with the G/G promoter polymorphism produced higher levels of beta-chemokines after in vitro stimulation. Thus, the CCR5 -2459 (A/G) promoter polymorphism determines CCR5 expression and predicts the magnitude of HIV-1 propagation in vitro. These findings may provide important insight regarding the regulation of mechanisms that influence the rate of HIV-1 propagation and progression to AIDS.

Cell Division↗
PubMed2003

Two mechanisms for human immunodeficiency virus type 1 inhibition by N-terminal modifications of RANTES.

C-C chemokine receptor 5 (CCR5) is the primary coreceptor for human immunodeficiency virus type 1 (HIV-1) infection. Native chemokines that bind to CCR5 inhibit HIV-1 infection, albeit weakly, but chemically modified chemokines inhibit infection more efficiently. We have investigated the inhibitory mechanism of three N-terminally modified RANTES variants (AOP-, NNY-, and PSC-RANTES) with the MT-2 human T-cell line stably expressing either native or mutated CCR5. The RANTES analogues showed the same rank order (PSC > NNY > AOP) in their capacity to induce prolonged CCR5 internalization, inhibit surface reexpression, and prevent HIV-1 infection on MT-2 cells expressing wild-type CCR5 or CCR5 with four C-terminal serine phosphorylation sites mutated to alanine. None of the RANTES analogues caused internalization of a C-terminal cytoplasmic domain deletion mutant of CCR5, and each derivative had equal potency in inhibiting HIV-1 infection of MT-2 cells expressing this mutant. We conclude that the C-terminal cytoplasmic residues of CCR5 are necessary for receptor sequestration by RANTES analogues but that the process and the relative activity of each derivative are not dependent upon phosphorylation of the C-terminal serine residues. Two mechanisms of antiviral activity are demonstrated: receptor blockade and receptor sequestration. Potency correlates with the ability to induce CCR5 sequestration but not with receptor binding, suggesting that sequestration may make the greater contribution to antiviral activity.

Anti-HIV Agents↗
PubMed2002

Characterization of human immunodeficiency virus type 1 (HIV-1) Gag- and Gag peptide-specific CD4(+) T-cell clones from an HIV-1-seronegative donor following in vitro immunization.

Substantial evidence argues that human immunodeficiency virus type 1 (HIV-1)-specific CD4(+) T cells play an important role in the control of HIV-1 replication in infected individuals. Moreover, it is increasingly clear that an HIV vaccine should elicit potent cytotoxic lymphocyte and antibody responses that will likely require an efficient CD4(+) T-cell response. Therefore, understanding and characterizing HIV-specific CD4(+) T-cell responses is an important aim. Here we describe the generation of HIV-1 Gag- and Gag peptide-specific CD4(+) T-cell clones from an HIV-1-seronegative donor by in vitro immunization with HIV-1 Gag peptides. The Gag peptides were able to induce a strong CD4(+) T-cell immune response in peripheral blood mononuclear cells from the HIV-1-seronegative donor. Six Gag peptide-specific CD4(+) T-cell clones were isolated and their epitopes were mapped. The region of p24 between amino acids 201 and 300 of Gag was defined as the immunodominant region of Gag. A new T helper epitope in the p6 protein of Gag was identified. Two clones were shown to recognize Gag peptides and processed Gag protein, while the other four clones reacted only to Gag peptides under the experimental conditions used. Functional analysis of the clones indicated that both Th1 and Th2 types of CD4(+) T cells were obtained. One clone showed direct antigen-specific cytotoxic activity. These clones represent a valuable tool for understanding the cellular immune response to HIV-1, and the study provides new insights into the HIV-1-specific CD4(+) T-cell response and the induction of an anti-Gag and -Gag peptide cellular primary immune response in vitro.

AIDS Vaccines↗