RESUMEN
The aim of this study was to understand factors associated with increased mortality in a cohort of primary HIV infection (PHI) in New South Wales (NSW) over three decades. Six hundred and two patients with PHI were enrolled from 1984 to 2009. Probabilistic data linkage was performed to NSW Registry of births deaths and marriages and Australian Bureau of Statistics mortality database. Mortality was measured by crude death rate. Pre highly active antiretroviral therapy (pre-HAART) era was defined as before January 1, 1997. A Cox proportional hazard model was used to identify factors associated with death. One hundred and thirty-eight deaths occurred during 6,223 person years (PY) follow-up. Overall crude death rate was 2.2 per 100 PY (95% confidence interval [CI], 1.9-2.6), 3.6 (95% CI, 3.1-4.3)in pre-HAART era and 0.20 (95% CI, 0.08-0.47) in post-HAART era. AIDS was the most frequent cause of death (52%, 72/138), all occurring in the pre-HAART era. Of non-AIDS deaths, the leading known cause was non-AIDS cancer 8% (11/138) followed by suicide 4% (6/138). On multivariate analysis, estimated date of infection in pre-HAART era and time to commencement of ART greater than 1 year post diagnosis were more likely to be associated with death (p < .05). Mortality in PHI has decreased significantly in the post-HAART era. Non-AIDS deaths due to malignancy and suicide are emerging as leading causes in this population in the post-HAART era. Time to starting ART greater than 1 year was associated with increased mortality.
Asunto(s)
Terapia Antirretroviral Altamente Activa/estadística & datos numéricos , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/mortalidad , Adulto , Fármacos Anti-VIH/uso terapéutico , Australia/epidemiología , Recuento de Linfocito CD4 , Causas de Muerte , Estudios de Cohortes , Femenino , VIH , Humanos , Masculino , Análisis de SupervivenciaRESUMEN
BACKGROUND: Latently infected resting memory CD4 T cells are thought to be the major reservoir that contributes to rebound viremia after cessation of antiretrovirals (ARVs). Commencing ARVs during primary HIV-1 infection (PHI) may limit the size of the latent pool and lead to improved control of viral replication during structured treatment interruption (STI). METHODS: Individuals with PHI (n = 59) were randomized to receive ARVs with or without hydroxyurea. After STI, a good response was defined as maintenance of HIV-1 RNA <5000 copies/mL for 24 weeks off therapy. In a detailed prospective virologic substudy (n = 19), integrated HIV-1 DNA, total HIV-1 DNA, and cell-associated HIV-1 unspliced (US) RNA were quantified using a real-time polymerase chain reaction assay. RESULTS: The plasma HIV-1 RNA 12 weeks after the initiation of ARVs was significantly lower in good responders (n = 7) compared with poor responders (n = 12) (P = 0.005). There were no significant differences between good and poor responders in integrated HIV-1 DNA, HIV-1 DNA, and HIV-1 US RNA. Integrated HIV-1 DNA before initiation of ARVs was strongly correlated with plasma HIV-1 RNA at week 12 (P = 0.006, r = 0.81). CONCLUSION: HIV-1 RNA measured 12 weeks after initiation of ARV was the only virologic variable associated with viral rebound after treatment interruption in PHI.
Asunto(s)
Fármacos Anti-VIH/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , VIH-1/efectos de los fármacos , Hidroxiurea/uso terapéutico , Viremia , Privación de Tratamiento , Adulto , ADN Viral/análisis , Quimioterapia Combinada , Humanos , ARN Viral/sangre , Resultado del Tratamiento , Estados Unidos , Integración ViralRESUMEN
BACKGROUND: Structured treatment interruptions (STIs) have been postulated to improve virologic control in primary HIV infection (PHI) by stimulating HIV-specific T-lymphocyte immunity. The addition of hydroxyurea (HU) may reduce viral production from activated CD4 cells. METHODS: Patients with PHI received a standardized antiretroviral (ARV) regimen consisting of indinavir 800 mg twice daily (BID), ritonavir 100 mg BID, didanosine 400 mg (QD), and either stavudine 40 mg BID or lamivudine 150 mg BID, for up to 12 months and were randomized to HU 500 mg BID or not. If viral suppression (<50 copies/mL) was achieved, up to 3 STIs were undertaken. Two ARV cycles were allowed after each interruption if virologic rebound to more than 5000 RNA copies/mL occurred. Treatment success was defined as maintaining viral loads below 5000 copies/mL for 6 months after ARV interruption. RESULTS: Sixty-eight male homosexual patients were randomized: 35 to ARV + HU and 33 to ARV-alone. Median baseline HIV RNA was 5.73 log10 copies/mL, and median CD4 T-lymphocyte count was 517 cells/microL. Treatment success was not significantly different between those receiving and not receiving HU, with 9 (26%) and 9 (27%), respectively, maintaining viral load at less than 5000 copies/mL in each group (P = 0.88). Virologic control was achieved by 11 (19%) of 59 after 1 STI, 1 (2%) of 41 after 2 STIs, and 6 (17%) of 36 after the third STI. Serious adverse events were recorded for 9 (26%) of 35 of patients using HU and 3 (9%) of 33 in the ARV-only group (P = 0.28). CD4 cell increases were significantly blunted for the HU group compared to the ARV-alone group after the initial treatment phase (+101 cells vs. +196 cells, respectively, P = 0.006). CONCLUSIONS: Hydroxyurea was not found to be beneficial when used in association with STIs in patients during PHI.
Asunto(s)
Fármacos Anti-VIH/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Hidroxiurea/uso terapéutico , Adulto , Fármacos Anti-VIH/administración & dosificación , Fármacos Anti-VIH/efectos adversos , Fármacos Anti-VIH/farmacología , Recuento de Linfocito CD4 , Esquema de Medicación , Quimioterapia Combinada , VIH/efectos de los fármacos , Homosexualidad , Humanos , Hidroxiurea/administración & dosificación , Hidroxiurea/efectos adversos , Hidroxiurea/farmacología , Masculino , ARN Viral/sangre , Resultado del Tratamiento , Carga ViralRESUMEN
We recently found that human immunodeficiency virus (HIV)-specific CD4+ T cells express coreceptor CCR5 and activation antigen CD38 during early primary HIV-1 infection (PHI) but then rapidly disappear from the circulation. This cell loss may be due to susceptibility to infection with HIV-1 but could also be due to inappropriate apoptosis, an expansion of T regulatory cells, trafficking out of the circulation, or dysfunction. We purified CD38+++CD4+ T cells from peripheral blood mononuclear cells, measured their level of HIV-1 DNA by PCR, and found that about 10% of this population was infected. However, a small subset of HIV-specific CD4+) T cells also expressed CD127, a marker of long-term memory cells. Purified CD127+CD4+ lymphocytes contained fivefold more copies of HIV-1 DNA per cell than did CD127-negative CD4+ cells, suggesting preferential infection of long-term memory cells. We observed no apoptosis of antigen-specific CD4+ T cells in vitro and only a small increase in CD45RO+CD25+CD127dimCD4+ T regulatory cells during PHI. However, 40% of CCR5+CD38+++ CD4+ T cells expressed gut-homing integrins, suggesting trafficking through gut-associated lymphoid tissue (GALT). Furthermore, 80% of HIV-specific CD4+ T cells expressed high levels of the negative regulator CTLA-4 in response to antigen stimulation in vitro, which was probably contributing to their inability to produce interleukin-2 and proliferate. Taken together, the loss of HIV-specific CD4+ T cells is associated with a combination of an infection of CCR5+ CD127+ memory CD4+ T cells, possibly in GALT, and a high expression of the inhibitory receptor CTLA-4.
Asunto(s)
Antígenos de Diferenciación/biosíntesis , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/virología , Infecciones por VIH/inmunología , VIH-1/inmunología , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/virología , ADP-Ribosil Ciclasa 1/análisis , Adulto , Antígenos CD , Antígeno CTLA-4 , ADN Viral/análisis , ADN Viral/genética , Citometría de Flujo , VIH-1/genética , VIH-1/fisiología , Humanos , Antígenos Comunes de Leucocito/análisis , Masculino , Reacción en Cadena de la Polimerasa , Proteína Tirosina Fosfatasa no Receptora Tipo 1 , Receptores CCR5/análisis , Receptores de Interleucina-2/análisis , Receptores de Interleucina-7/análisis , Linfocitos T Reguladores/inmunologíaRESUMEN
We investigated whether HIV-1 antigen-specific CD4(+) T cells expressed the viral coreceptor CCR5 during primary HIV-1 infection (PHI). In the peripheral blood of subjects with very early PHI (< 22 days after onset of symptoms), there was a 10- to 20-fold increase in the proportion of highly activated (CD38(+++)) and proliferating (Ki-67(+)) CD4(+) T cells that expressed CCR5(+), and were mostly T-cell intracellular antigen-1 (TIA-1)(+) perforin(+) granzyme B(+). Inthe same patient samples, CD4(+) T cells producing interferon (IFN)-gamma in response to HIV group-specific antigen (Gag) peptides were readily detected (median, 0.58%) by intracellular cytokine assay-these cells were again predominantly CD38(+++), Ki-67(+), and TIA-(++), as well as Bcl-2(low). On average, 20% of the Gag-specific CD4(+) T cells also expressed interleukin-2 (IL-2) and were CD127 (IL-7R)(+). Taken together, these results suggest that Gag-specific T-helper 1 (Th1) effector cells express CCR5 during the primary response and may include precursors of long-term self-renewing memory cells. However, in PHI subjects with later presentation, antigen-specific CD4(+) T cells could not be readily detected (median, 0.08%), coinciding with a 5-fold lower level of the CCR5(+)CD38(+++) CD4(+) T cells. These results suggest that the antiviral response to HIV-1 infection includes highly activated CCR5(+)CD4(+) cytotoxic effector cells, which are susceptible to both apoptosis and cytopathic infection with HIV-1, and rapidly decline.
Asunto(s)
ADP-Ribosil Ciclasa/inmunología , Antígenos CD/inmunología , Linfocitos T CD4-Positivos/inmunología , Infecciones por VIH/inmunología , VIH-1/inmunología , Receptores CCR5/inmunología , Células TH1/inmunología , ADP-Ribosil Ciclasa/sangre , ADP-Ribosil Ciclasa 1 , Adulto , Antígenos CD/sangre , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD4-Positivos/virología , Proliferación Celular , Infecciones por VIH/virología , Humanos , Masculino , Glicoproteínas de Membrana , Fenotipo , Receptores CCR5/sangre , Células TH1/metabolismo , Células TH1/virologíaRESUMEN
The cytotoxic potential of CD8(+) T cells and NK cells plays a crucial role in the immune response to pathogens. Although in vitro studies have reported that CD4(+) T cells are also able to mediate perforin-mediated killing, the in vivo existence and relevance of cytotoxic CD4(+) T cells have been the subject of debate. Here we show that a population of CD4(+) perforin(+) T cells is present in the circulation at low numbers in healthy donors and is markedly expanded in donors with chronic viral infections, in particular HIV infection, at all stages of the disease, including early primary infection. Ex vivo analysis shows that these cells have cytotoxic potential mediated through the release of perforin. In comparison with more classical CD4(+) T cells, this subset displays a distinct surface phenotype and functional profile most consistent with end-stage differentiated T cells and include Ag experienced CD4(+) T cells. The existence of CD4(+) cytotoxic T cells in vivo at relatively high levels in chronic viral infection suggests a role in the immune response.
Asunto(s)
Antígenos CD4/análisis , Linfocitos T Citotóxicos/inmunología , Linfocitos T CD8-positivos/inmunología , Enfermedad Crónica , Infecciones por VIH/inmunología , Humanos , Glicoproteínas de Membrana/análisis , Perforina , Proteínas Citotóxicas Formadoras de PorosRESUMEN
We measured apoptosis of subsets of T lymphocytes by single-cell analysis of caspase activation, to confirm high turnover of chemokine receptor CCR5(+) T cells in subjects with acute, primary human immunodeficiency virus type 1 (HIV-1) infection (PHI). High levels of spontaneous apoptosis, consisting mainly of CD8(+) T lymphocytes, were closely associated with increases in the activation markers Ki-67, CD38, and the HIV coreceptor CCR5 and with decreases in Bcl-2 and the interleukin (IL)-7 receptor at the single-cell level. Increased expression of Ki-67 and CCR5 ex vivo, as well as increased apoptosis, was seen in all T cell receptor beta-chain variable region (TCRBV) subfamilies studied. The addition of IL-2 or IL-15, but not IL-7, significantly inhibited caspase activation, increased Bcl-2 expression, and rapidly initiated proliferation in vitro of CD8(+) T cells expressing CCR5 and multiple TCRBV subfamilies. Furthermore, IL-15 receptor alpha-chain messenger RNA levels were increased in peripheral blood mononuclear cells during PHI. These results suggest that CCR5(+)Ki-67(+)Bcl-2(dim) activated T cells generated during PHI traffic via blood to tissue sites, where the cells may survive and/or further proliferate under the local influence of IL-2 or IL-15. Understanding cytokine effects on CCR5(+) T cells will be important in understanding chronic HIV-1 replication and pathogenesis.