Search PubMed⌕ Search

Biomedical subjects

Brian Gazzard

Publications and source records attributed to Brian Gazzard.

87 records · Page 5Linked to original sources
PubMed2003

Thymic output during initial highly active antiretroviral therapy (HAART) and during HAART supplementation with interleukin 2 and/or with HIV type 1 immunogen (Remune).

The thymic output of patients receiving highly active antiretroviral therapy (HAART) was assessed by sjTREC (signal joint T cell receptor rearrangement excision circle) analysis to determine the thymic contribution to CD4(+) T cell reconstitution during initial therapy and during interleukin 2 (IL-2) and/or Remune supplementation of HAART. Levels of sjTRECs were observed to decline dramatically after the first 4 weeks of HAART and then increased without significant associated changes in CD4(+) T cell counts. HAART supplementation with IL-2 was observed to lead to rapid increases in CD4(+) T cells that were accompanied by sjTREC decreases. No notable changes in CD4(+) T cell counts and sjTRECs were seen in patients receiving HAART supplemented with Remune alone. The results indicate CD4(+) T cell maintenance during initial treatment of HIV-1 with HAART and early CD4(+) T cell reconstitution of patients receiving IL-2 with HAART is largely due to thymus-independent mechanisms, with the thymus making a limited contribution.

AIDS Vaccines↗
PubMed2003

Innate and adaptive immunological insights into HIV pathogenesis.

The human immunodeficiency virus is notorious for its ability to evade the immune system. As well as its ability to escape from cell-mediated and humoral immune responses, new insights are detailing its subversive, pernicious interactions with the innate immune system. The molecular mechanisms underlying these processes highlight potential therapeutic and vaccination strategies.

Antibody Formation↗
PubMed2003

Current treatment of HIV infection.

The field of antiretroviral therapy has witnessed remarkable progress during the past 15 years. There are now over a dozen approved therapeutic agents for infection with the human immunodeficiency virus (HIV), a pathogen that once caused nearly uniformly fatal illness. These agents usually target two essential enzymes of the virus, the reverse transcriptase and the protease. The era of potent antiretroviral therapy, also termed highly active antiretroviral therapy, began in 1996 and has been marked by dramatic declines in morbidity and mortality due to HIV disease in the developed world. These advances have not been without their cost in terms of drug resistance and toxicity and unwanted effects. Concern about these negative effects has led to a more conservative approach to the timing of the initiation of therapy and to clinical trials of intermittent therapy in an attempt to decrease the total exposure to drugs over time. Immune-based approaches such as therapeutic vaccination may someday permit viremia to be controlled in the absence of drugs. Antiviral potency has been the key to the initial success of drug regimens, as well as to the durability of their success, the restoration of immune function, the prevention of the emergence of resistance, and ultimately the prevention of disease progression. Future progress in antiretroviral therapy will bring more choices for physicians and patients and will make an already complex field both more challenging and more rewarding.

Anti-HIV Agents↗
PubMed2002

Prospective study of the effects of antiretroviral therapy on Kaposi sarcoma--associated herpesvirus infection in patients with and without Kaposi sarcoma.

OBJECTIVE: To investigate the effect of highly active antiretroviral therapy (HAART) on circulating Kaposi sarcoma (KS)-associated herpesvirus (KSHV) load in HIV-infected individuals with and without KS. DESIGN: Twenty-nine HIV-infected subjects (21 with KS and 8 without KS) were recruited for the study; they were prospectively studied before and at regular intervals during HAART. METHODS: Patients with KS were clinically assessed using Adult Clinical Trials Group (ACTG) criteria, and sequential blood samples were obtained from all patients for determination of plasma HIV-1 load, CD4 cell count, titer of antibody to KSHV, and KSHV load. RESULTS: Ten of 21 patients with KS had a favorable KS response (complete response, 6; partial response, 4) with HAART alone. Of the 20 subjects with detectable KSHV viremia prior to HAART, over one half (12 [60%]) had an undetectable KSHV load with antiretroviral therapy. There was no significant difference between subjects receiving protease inhibitor- or nonnucleoside reverse transcriptase inhibitor-based treatment combinations. Achieving undetectable KSHV viremia is associated with a better clinical outcome in patients with KS. CONCLUSIONS: To our knowledge, we demonstrate for the first time that both protease inhibitor-based and nonnucleoside reverse transcriptase inhibitor-based antiretroviral treatment combinations may lead to an undetectable KSHV load and confirm that an undetectable KSHV load is associated with KS regression. There was no clear association between CD4 cell count response and KS response to HAART, but there was a significant relationship between HIV load response to HAART and clinical improvement of KS.

Adult↗
PubMed2002

The immunological effects of concomitant highly active antiretroviral therapy and liposomal anthracycline treatment of HIV-1-associated Kaposi's sarcoma.

A combination of highly active antiretroviral therapy (HAART) and liposomal anthracycline chemotherapy is the standard of care for advanced HIV-associated Kaposi's sarcoma, despite concerns that the chemotherapy may adversely affect lymphocyte subsets and HIV viraemia. We showed in 50 patients that liposomal anthracyclines used with HAART did not lead to a significant loss of CD4 or CD8 cells or an increase in HIV-1 viral load during or up to 12 months after chemotherapy.

Adult↗
PubMed2002

The prevalence and determinants of the K65R mutation in HIV-1 reverse transcriptase in tenofovir-naive patients.

The K65R mutation in HIV-1 reverse transcriptase is associated with reduced susceptibility to abacavir and tenofovir. We established its prevalence within a large clinical database, and investigated correlations with other resistance-associated mutations and antiretroviral history. The presence of K65R is associated with previous abacavir use. Although rare, it is preferentially selected within non-thymidine analogue-containing regimens, compared with concurrent zidovudine or stavudine use, which is associated with thymidine analogue mutations. Both genetic routes may compromise abacavir and tenofovir activity.

Adenine↗
PubMed2002

Low levels of perforin expression in CD8+ T lymphocyte granules in lymphoid tissue during acute human immunodeficiency virus type 1 infection.

Human immunodeficiency virus (HIV)-specific cytotoxic T lymphocyte (CTL) responses are detectable shortly after the acute phase of HIV infection, but they cannot control viral replication and prevent development of chronic immune suppression. This article describes a defect in the coexpression of perforin in granzyme A-positive CD8(+) T cells in lymphoid tissue from patients with acute HIV infection and a reduction in the perforin-dependent nuclear translocation of granzyme A. Furthermore, intracellular levels of HIV DNA and RNA found in lymphoid tissue were higher (10-100 times) than those found in blood, and blood samples showed more-coordinated cellular perforin/granzyme A expression. This suggests that mechanisms inhibiting CTL-mediated cytotoxicity are operative in lymphoid tissue early in the course of HIV infection.

Acquired Immunodeficiency Syndrome↗
PubMed2002

Accumulation of DC-SIGN+CD40+ dendritic cells with reduced CD80 and CD86 expression in lymphoid tissue during acute HIV-1 infection.

BACKGROUND: Dendritic cells (DC) are target cells for HIV-1 and play a key role in antigen presentation and activation of T cells. OBJECTIVE: To characterize interdigitating DC in lymphoid tissue (LT) with regard to maturation, expression of cytokines and co-stimulatory molecules in HIV-1-positive patients. METHODS: DC were characterized by immunohistochemistry and in situ imaging in LT from patients with acute HIV-1 infection (aHI), antiretroviral treated patients, long-term non-progressors/slow progressors with HIV-1 infection (LTNP/SLP), patients with AIDS, HIV-1-negative controls and patients with acute Epstein-Barr virus (EBV) infection. RESULTS: A significant increase of interdigitating DC expressing CD1a, S-100b, CD83 and DC-SIGN was found in LT from patients with aHI (P < 0.02). The co-stimulatory molecules CD80 and CD86 were, however, only partially upregulated and the complete parafollicular network found in acute EBV infection was not generated, despite increased expression of interleukins 1alpha, 1beta, 12; interleukin 1alpha receptor antagonist; interferon alpha; and CD40 expression. LTNP/SLP and treated aviremic subjects had increased frequency of interdigitating DC, albeit lower than in aHI, and low expression of CD80 and CD86. In contrast, patients with AIDS had fewer DC and reduced cytokine expression in LT. CONCLUSIONS: In the early phase of HIV-1 infection, there was a migration of DC to LT comparable to that found in acute EBV infection. The infiltration of DC in LT in acute EBV infection was accompanied by upregulation of CD80 and CD86 expression, which did not occur in aHI. This co-stimulatory defect in aHI may have an impact on the development of HIV-1-specific T cell immunity.

Acute Disease↗
PubMed2002

A balanced type 1/type 2 response is associated with long-term nonprogressive human immunodeficiency virus type 1 infection.

Previous reports have emphasized the requirements for strong type 1 cell-mediated responses in the control of human immunodeficiency virus type 1 (HIV-1). HIV-1 Gag p24-specific CD4 helper T-lymphocyte (HTL) responses have been shown to inversely correlate with viral burden in HIV-1-infected individuals. In this study, peripheral blood mononuclear cells from 70 individuals with chronic progressive HIV-1 infection (clinical progressors), 10 clinical nonprogressors, and 3 immunologically discordant progressors were assessed for HTL proliferation and type 1/type 2 cytokine production. Clinical progressors lacked functional HIV-1-specific HTLs with proliferative and cytokine-producing capacity. Clinical nonprogressors were found to respond to a wide range of HIV-1 antigens from different clades, producing both type 1 and type 2 cytokines. Immunologically discordant progressors responded strongly to clade B Gag p24 with a type 1 cytokine profile but not to other antigens. Thus, in contrast to clinical nonprogressors, neither progressors nor immunologically discordant progressors secreted interleukin-4 (IL-4) in response to HIV-1 antigens. Both clinical nonprogressors and immunologically discordant progressors responded broadly to B clade Gag p24-overlapping peptides. However, IL-4 production in the nonprogressors was restricted to a limited number of p24 peptides. No HIV-1-specific T-cell responses were seen in 20 seronegative controls. Additionally, we observed a rapid type 1 to type 2 shift in the response of one immunologically discordant progressor upon onset of clinical symptoms. These results suggest that a balanced type 1/type 2 profile correlates with successful long-term control of HIV-1.

CD4-Positive T-Lymphocytes↗
PubMed2002

Identification of Kaposi's sarcoma-associated herpesvirus (KSHV)-specific cytotoxic T-lymphocyte epitopes and evaluation of reconstitution of KSHV-specific responses in human immunodeficiency virus type 1-Infected patients receiving highly active antiretroviral therapy.

Following the introduction of highly active antiretroviral therapy (HAART), the incidence of Kaposi's sarcoma (KS) has significantly declined in human immunodeficiency virus type 1 (HIV-1)-positive (HIV-1(+)) individuals and clinical remission is often observed. We hypothesize that these effects are partly due to anti-KS-associated herpesvirus (KSHV) immune restoration. Here, 15-mer overlapping peptides from proteins K12 and K8.1 were used to identify novel KSHV-specific cytotoxic T-lymphocyte epitopes. Three immunogenic peptides, two lytic and one latent, were subsequently used to monitor the anti-KSHV CD8(+) T-cell responses in a cohort of 19 HIV-1(+) KSHV(+/-) KS(+/-) individuals during 52 weeks of HAART. KSHV and HIV-1 loads, KSHV antibody titers, and both CD4(+) and CD8(+) T-lymphocyte counts were enumerated. Prior to HAART, the total number of spot-forming cells (SFC) for all three peptides correlated with both CD4(+) and CD8(+) T-lymphocyte counts (P < or = 0.05) in the KSHV-positive KS-positive cohort (n = 11). Following 52 weeks of HAART, significant decreases in HIV-1 and KSHV loads were associated with significant increases in CD4(+) T-lymphocyte counts and number of SFC for the three KSHV-specific peptides. Although these increases were modest in comparison to the number of SFC observed with the HIV-1 gag peptide SLYNTVATL, they represented a fourfold increase from the baseline, continuing an upward trend to week 52.

AIDS-Related Opportunistic Infections↗