Reduction in CD8+ cell noncytotoxic anti-HIV activity in individuals receiving highly active antiretroviral therapy during primary infection.

Recent advances in the ability to detect people at the early stages of HIV infection now permit the initiation of antiretroviral treatment before the full complement of antiviral immune responses has evolved. However, the influence of early treatment interventions on the developing anti-HIV immune response is unknown. This study investigates the impact of standard highly active antiretroviral therapy (HAART) during the primary stages of HIV infection on the plasma HIV-1 RNA level, CD4(+) and CD8(+) lymphocyte counts, and the CD8(+) cell anti-HIV response. Individuals treated with HAART within 6 months of infection showed dramatic and rapid reductions in HIV-1 RNA levels along with modest increases in CD4(+) cell number and decreases in CD8(+) cell numbers. A significant reduction in the level of CD8(+) cell noncytotoxic suppression of HIV replication was observed over time in most participants receiving HAART. Importantly, those individuals choosing not to receive therapy maintained low but detectable HIV-1 RNA levels and showed no reduction in their CD8(+) cell antiviral response. These results suggest that either continued antigenic challenge is required to sustain CD8(+) cell-mediated anti-HIV activity, or that HAART has some inhibitory effect on this important immunologic function during the early stages of infection.

[1]  C. Crumpacker,et al.  Inhibition of immune functions by antiviral drugs. , 1991, The Journal of clinical investigation.

[2]  G A Satten,et al.  New testing strategy to detect early HIV-1 infection for use in incidence estimates and for clinical and prevention purposes. , 1998, JAMA.

[3]  G. Shaw,et al.  Virus-specific CD8+ cytotoxic T-lymphocyte activity associated with control of viremia in primary human immunodeficiency virus type 1 infection , 1994, Journal of virology.

[4]  J. Levy,et al.  Rapid CD8+ Cell Anti-HIV Activity Correlates with the Clinical State of the Infected Individual , 2003 .

[5]  D. Ho,et al.  Temporal association of cellular immune responses with the initial control of viremia in primary human immunodeficiency virus type 1 syndrome , 1994, Journal of virology.

[6]  J. Lifson,et al.  Non-cytolytic CD8 T-cell anti-HIV responses in primary HIV-1 infection , 1994, The Lancet.

[7]  B. Yip,et al.  Decline in deaths from AIDS due to new antiretrovirals , 1997, The Lancet.

[8]  J. Levy,et al.  Isolation of lymphocytopathic retroviruses from San Francisco patients with AIDS. , 1984, Science.

[9]  B. Walker,et al.  Acute human immunodeficiency virus type 1 infection. , 1998, The New England journal of medicine.

[10]  John W. Mellors,et al.  Prognosis in HIV-1 Infection Predicted by the Quantity of Virus in Plasma , 1996, Science.

[11]  C. Pitcher,et al.  HIV-1-specific CD4+ T cells are detectable in most individuals with active HIV-1 infection, but decline with prolonged viral suppression , 1999, Nature Medicine.

[12]  J. Berzofsky,et al.  Cell-mediated immune response to human immunodeficiency virus (HIV) type 1 in seronegative homosexual men with recent sexual exposure to HIV-1. , 1992, The Journal of infectious diseases.

[13]  E. Vittinghoff,et al.  Impact of protease inhibitors and other antiretroviral treatments on acquired immunodeficiency syndrome survival in San Francisco, California, 1987-1996. , 2000, American journal of epidemiology.

[14]  J. Levy,et al.  Recovery of AIDS-associated retroviruses from patients with AIDS or AIDS-related conditions and from clinically healthy individuals. , 1985, The Journal of infectious diseases.

[15]  J. Levy,et al.  MT-4 plaque formation can distinguish cytopathic subtypes of the human immunodeficiency virus (HIV). , 1988, Virology.

[16]  S. Hammer,et al.  A trial comparing nucleoside monotherapy with combination therapy in HIV-infected adults with CD4 cell counts from 200 to 500 per cubic millimeter. AIDS Clinical Trials Group Study 175 Study Team. , 1996, The New England journal of medicine.

[17]  J. Levy,et al.  Role of β-Chemokines in Suppressing HIV Replication , 1996, Science.

[18]  G. Satten,et al.  Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. , 1998, The New England journal of medicine.

[19]  J. Skurnick,et al.  Lack of infection in HIV-exposed individuals is associated with a strong CD8(+) cell noncytotoxic anti-HIV response. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[20]  J. Levy,et al.  Optimal conditions for recovery of the human immunodeficiency virus from peripheral blood mononuclear cells , 1988, Journal of clinical microbiology.

[21]  Roger Detels,et al.  Plasma Viral Load and CD4+ Lymphocytes as Prognostic Markers of HIV-1 Infection , 1997, Annals of Internal Medicine.

[22]  M. Peeters,et al.  Efficiencies of Four Versions of the AMPLICOR HIV-1 MONITOR Test for Quantification of Different Subtypes of Human Immunodeficiency Virus Type 1 , 1999, Journal of Clinical Microbiology.

[23]  J. Levy,et al.  Characterization of the AIDS-associated retrovirus reverse transcriptase and optimal conditions for its detection in virions. , 1985, Virology.

[24]  J. Mellors,et al.  3-Year Suppression of HIV Viremia with Indinavir, Zidovudine, and Lamivudine , 2000, Annals of Internal Medicine.

[25]  M. Clerici,et al.  Protective immunity against HIV infection: has nature done the experiment for us? , 1996, Immunology today.

[26]  D. Ho,et al.  HIV-1 Antigen–specific and –nonspecific B Cell Responses Are Sensitive to Combination Antiretroviral Therapy , 1998, The Journal of experimental medicine.

[27]  J. Moore,et al.  The effect of commencing combination antiretroviral therapy soon after human immunodeficiency virus type 1 infection on viral replication and antiviral immune responses. , 1999, The Journal of infectious diseases.

[28]  S. Rowland-Jones,et al.  HIV-specific cytotoxic T-cells in HIV-exposed but uninfected Gambian women , 1995, Nature Medicine.

[29]  K. Harada,et al.  Direct Observation of Vortex Dynamics in Superconducting Films with Regular Arrays of Defects , 1996, Science.

[30]  A Muñoz,et al.  Effectiveness of potent antiretroviral therapy on time to AIDS and death in men with known HIV infection duration. Multicenter AIDS Cohort Study Investigators. , 1998, JAMA.

[31]  T. Merigan,et al.  Treatment of human immunodeficiency virus infection with saquinavir, zidovudine, and zalcitabine. AIDS Clinical Trials Group. , 1996, The New England journal of medicine.

[32]  D. Dimitrov,et al.  Cell-to-cell spread of HIV-1 occurs within minutes and may not involve the participation of virus particles. , 1992, Virology.

[33]  E. Rosenberg,et al.  Vigorous HIV-1-specific CD4+ T cell responses associated with control of viremia. , 1997, Science.

[34]  D. Cooper,et al.  CD8+ anti-human immunodeficiency virus suppressor activity (CASA) in response to antiretroviral therapy: loss of CASA is associated with loss of viremia. , 1999, The Journal of infectious diseases.

[35]  D. Hawkins,et al.  A controlled trial of zidovudine in primary human immunodeficiency virus infection. , 1995, The New England journal of medicine.

[36]  H. Sheppard,et al.  Circulating HIV-1-infected cell burden from seroconversion to AIDS: importance of postseroconversion viral load on disease course. , 1994, Journal of acquired immune deficiency syndromes.

[37]  J. Berzofsky,et al.  HIV-specific T-helper activity in seronegative health care workers exposed to contaminated blood. , 1994, JAMA.

[38]  E A Emini,et al.  Treatment with indinavir, zidovudine, and lamivudine in adults with human immunodeficiency virus infection and prior antiretroviral therapy. , 1997, The New England journal of medicine.

[39]  M. Niu,et al.  Primary human immunodeficiency virus type 1 infection: review of pathogenesis and early treatment intervention in humans and animal retrovirus infections. , 1993, The Journal of infectious diseases.

[40]  P. Tovo.  Highly active antiretroviral therapy inhibits cytokine production in HIV-uninfected subjects. , 2000, AIDS.

[41]  D. Nixon,et al.  Changes in frequency of HIV-1-specific cytotoxic T cell precursors and circulating effectors after combination antiretroviral therapy in children. , 1999, The Journal of infectious diseases.