Immune control of HIV-1 after early treatment of acute infection

Virus-specific T-helper cells are considered critical for the control of chronic viral infections. Successful treatment of acute HIV-1 infection leads to augmentation of these responses, but whether this enhances immune control has not been determined. We administered one or two supervised treatment interruptions to eight subjects with treated acute infection, with the plan to restart therapy if viral load exceeded 5,000 copies of HIV-1 RNA per millilitre of plasma (the level at which therapy has been typically recommended) for three consecutive weeks, or 50,000 RNA copies per ml at one time. Here we show that, despite rebound in viraemia, all subjects were able to achieve at least a transient steady state off therapy with viral load below 5,000 RNA copies per ml. At present, five out of eight subjects remain off therapy with viral loads of less than 500 RNA copies per ml plasma after a median 6.5 months (range 5–8.7 months). We observed increased virus-specific cytotoxic T lymphocytes and maintained T-helper-cell responses in all. Our data indicate that functional immune responses can be augmented in a chronic viral infection, and provide rationale for immunotherapy in HIV-1 infection.

[1]  R. Young,et al.  Long-term culture and fine specificity of human cytotoxic T-lymphocyte clones reactive with human immunodeficiency virus type 1. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[2]  R. Zinkernagel,et al.  Enhanced establishment of a virus carrier state in adult CD4+ T-cell-deficient mice , 1994, Journal of virology.

[3]  Persephone Borrow,et al.  Major expansion of CD8+ T cells with a predominant Vβ usage during the primary immune response to HIV , 1994, Nature.

[4]  R. Ahmed,et al.  CD4+ T cells are required to sustain CD8+ cytotoxic T-cell responses during chronic viral infection , 1994, Journal of virology.

[5]  M. V. von Herrath,et al.  CD4-deficient mice have reduced levels of memory cytotoxic T lymphocytes after immunization and show diminished resistance to subsequent virus challenge , 1996, Journal of virology.

[6]  S. Hammer,et al.  Antiretroviral therapy for HIV infection in 1997. Updated recommendations of the International AIDS Society-USA panel. , 1998, JAMA.

[7]  J Leibowitch,et al.  Positive effects of combined antiretroviral therapy on CD4+ T cell homeostasis and function in advanced HIV disease. , 1997, Science.

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

[9]  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.

[10]  M. Houghton,et al.  Recurrence of hepatitis C virus after loss of virus specific CD4+ T cell response in acute hepatitis C , 1998 .

[11]  J. Altman,et al.  Viral Immune Evasion Due to Persistence of Activated T Cells Without Effector Function , 1998, The Journal of experimental medicine.

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

[13]  Spyros A. Kalams,et al.  The Critical Need for CD4 Help in Maintaining Effective Cytotoxic T Lymphocyte Responses , 1998, The Journal of experimental medicine.

[14]  R. Steinman,et al.  Rapid generation of broad T-cell immunity in humans after a single injection of mature dendritic cells. , 1999, The Journal of clinical investigation.

[15]  T. Santantonio,et al.  Recurrence of hepatitis C virus after loss of virus-specific CD4(+) T-cell response in acute hepatitis C. , 1999, Gastroenterology.

[16]  B. Walker,et al.  Levels of Human Immunodeficiency Virus Type 1-Specific Cytotoxic T-Lymphocyte Effector and Memory Responses Decline after Suppression of Viremia with Highly Active Antiretroviral Therapy , 1999, Journal of Virology.

[17]  J. Lisziewicz,et al.  Treatment of human immunodeficiency virus infection with hydroxyurea, didanosine, and a protease inhibitor before seroconversion is associated with normalized immune parameters and limited viral reservoir. , 1999, The Journal of infectious diseases.

[18]  R. Lempicki,et al.  HIV-1 and T cell dynamics after interruption of highly active antiretroviral therapy (HAART) in patients with a history of sustained viral suppression. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[19]  Todd M. Allen,et al.  Virus-specific cytotoxic T-lymphocyte responses select for amino-acid variation in simian immunodeficiency virus Env and Nef , 1999, Nature Medicine.

[20]  A. Trkola,et al.  HIV-1-specific immune responses in subjects who temporarily contain virus replication after discontinuation of highly active antiretroviral therapy. , 1999, The Journal of clinical investigation.

[21]  E. Rosenberg,et al.  Reduced antiretroviral drug susceptibility among patients with primary HIV infection. , 1999, JAMA.

[22]  J. Lisziewicz,et al.  Control of HIV despite the discontinuation of antiretroviral therapy. , 1999, The New England journal of medicine.

[23]  E. Rosenberg,et al.  Association between Virus-Specific Cytotoxic T-Lymphocyte and Helper Responses in Human Immunodeficiency Virus Type 1 Infection , 1999, Journal of Virology.

[24]  J. Martinez-Picado,et al.  Human Immunodeficiency Virus Type 1 Cloning Vectors for Antiretroviral Resistance Testing , 1999, Journal of Clinical Microbiology.

[25]  B. Walker,et al.  Analysis of Successful Immune Responses in Persons Infected with Hepatitis C Virus , 2000, The Journal of experimental medicine.

[26]  R H Lyles,et al.  Natural history of human immunodeficiency virus type 1 viremia after seroconversion and proximal to AIDS in a large cohort of homosexual men. Multicenter AIDS Cohort Study. , 2000, The Journal of infectious diseases.

[27]  P. Easterbrook,et al.  Early highly active antiretroviral therapy for acute HIV-1 infection preserves immune function of CD8+ and CD4+ T lymphocytes. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[28]  M. McElrath,et al.  Effect of combination antiretroviral therapy on T-cell immunity in acute human immunodeficiency virus type 1 infection. , 2000, The Journal of infectious diseases.

[29]  E. Rosenberg,et al.  Differential Narrow Focusing of Immunodominant Human Immunodeficiency Virus Gag-Specific Cytotoxic T-Lymphocyte Responses in Infected African and Caucasoid Adults and Children , 2000, Journal of Virology.