Immunologic Nonresponders: Suboptimal CD4 T-Cell Response in Antiretroviral-Treated, HIV-Infected Patients
Dr. Hiroyu Hatano discusses the mechanisms of suboptimal immune recovery in patients receiving antiretroviral treatment and offers suggestions for means of better understanding this increasingly important area of HIV research.
Given the increasing availability of antiretroviral drugs that can durably and safely suppress HIV replication, one of the major challenges in the next decade of HIV care will be to restore normal immunologic health. Suboptimal CD4 T-cell responses to antiretroviral therapy (ART) have been associated with substantial increases in the risk of AIDS-related and non-AIDS-related mortality and morbidity, including cardiovascular disease, liver disease, renal disease, and malignancies.(1, 2, 3) Unfortunately, a significant proportion of HIV-infected individuals are not able to achieve a normal CD4 T-cell count despite prolonged viral suppression with ART. In one study, approximately 25% of patients who started ART with a CD4 count of <200 cells/µL did not achieve a CD4 count of >500 cells/µL even after 7-10 years of treatment or longer.(4)
Several clinical factors have been associated with immunologic nonresponse, including older age, male gender, lower nadir CD4 count, and hepatitis C virus coinfection.(5, 6, 7) However, the mechanisms of suboptimal immune recovery are not completely understood.(8) Although there is an ongoing debate as to whether viral replication persists in the context of suppressive ART, the majority of treatment intensification studies have shown that ongoing low-level viral replication is not likely to be a significant contributor to immunologic nonresponse.(9, 10, 11, 12, 13) On the other hand, multiple studies have shown an association between T-cell activation and reduced CD4 cell recovery. Persistent T-cell activation (and ongoing microbial translocation) despite ART may lead to blunted CD4 cell gains owing to collagen deposition and its distorting effects on lymphoid tissue architecture.(14, 15, 16, 17) Indeed, the degree of local fibrosis in lymph nodes and gut-associated lymphoid tissue (GALT) has been shown to predict the degree of CD4 cell recovery with ART.(16, 17)
Moreover, although persistent viral replication may not play a significant role in incomplete CD4 T-cell recovery, HIV persists in lymph nodes and GALT despite long-term ART, and this persistent viral expression in lymphoid tissues may be the proximal cause of chronic immune activation during the course of ART.(18, 19, 20) Immunologic nonresponders may have a larger latent reservoir of HIV compared with responders (eg, owing to later presentation to care or initiation of ART), and most of this reservoir is likely to reside in the gut. Because of lymphoid fibrosis, nonresponders may have insufficient or ineffective HIV-specific responses in this critical location (where most of the residual virus persists), and thus may lack essential tools or means to control the size of the latent reservoir.(13) Immunologic nonresponders therefore may be caught in a self-sustaining and unrelenting cycle of increased immune activation, increased microbial translocation, and continuous damage and fibrosis in the gut, which in sum prevents full CD4 T-cell recovery.(15)
This key area of HIV research requires ongoing investigation and warrants the design of studies explicitly aimed at examining the mechanisms underlying immunologic nonresponse. One major limitation of such research has been a lack of uniformity in the definition of "immunologic nonresponder." Studies conducted to date generally have included any patient with a CD4 count of <350 cells/µL despite treatment-mediated viral load suppression for more than 1-2 years. Having a more precise and standardized definition will allow researchers to better understand the potential mechanisms underlying suboptimal CD4 T-cell recovery and to differentiate patients with low CD4 counts relatively early in the course of ART from those who are true long-term, immunologic nonresponders.
- El-Sadr WM, Lundgren JD, Neaton JD, et al; Strategies for Management of Antiretroviral Therapy (SMART) Study Group. CD4+ count-guided interruption of antiretroviral treatment. N Engl J Med. 2006 Nov 30;355(22):2283-96. PMID: 17135583.
- Moore DM, Hogg RS, Chan K, et al. Disease progression in patients with virological suppression in response to HAART is associated with the degree of immunological response. AIDS. 2006 Feb 14;20(3):371-7. PMID: 16439870.
- Baker JV, Peng G, Rapkin J, et al; Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA). CD4+ count and risk of non-AIDS diseases following initial treatment for HIV infection. AIDS. 2008 Apr 23;22(7):841-8. PMID: 18427202.
- Kelley CF, Kitchen CM, Hunt PW, et al. Incomplete peripheral CD4+ cell count restoration in HIV-infected patients receiving long-term antiretroviral treatment. Clin Infect Dis. 2009 Mar 15;48(6):787-94. PMID: 19193107.
- Greub G, Ledergerber B, Battegay M, et al. Clinical progression, survival, and immune recovery during antiretroviral therapy in patients with HIV-1 and hepatitis C virus coinfection: the Swiss HIV Cohort Study. Lancet. 2000 Nov 25;356(9244):1800-5. PMID: 11117912.
- Hunt PW, Deeks SG, Rodriguez B, et al. Continued CD4 cell count increases in HIV-infected adults experiencing 4 years of viral suppression on antiretroviral therapy. AIDS. 2003 Sep 5;17(13):1907-15. PMID: 12960823.
- Gandhi RT, Spritzler J, Chan E, et al; ACTG 384 Team. Effect of baseline- and treatment-related factors on immunologic recovery after initiation of antiretroviral therapy in HIV-1-positive subjects: results from ACTG 384. J Acquir Immune Defic Syndr. 2006 Aug 1;42(4):426-34. PMID: 16810109.
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- Havlir DV, Strain MC, Clerici M, et al. Productive infection maintains a dynamic steady state of residual viremia in human immunodeficiency virus type 1-infected persons treated with suppressive antiretroviral therapy for five years. J Virol. 2003 Oct;77(20):11212-9. PMID: 14512569.
- Dinoso JB, Kim SY, Wiegand AM, et al. Treatment intensification does not reduce residual HIV-1 viremia in patients on highly active antiretroviral therapy. Proc Natl Acad Sci U S A. 2009 Jun 9;106(23):9403-8. PMID: 19470482.
- Buzon MJ, Massanella M, Llibre JM, et al. HIV-1 replication and immune dynamics are affected by raltegravir intensification of HAART-suppressed subjects. Nat Med. 2010 Apr;16(4):460-5. PMID: 20228817.
- Gandhi RT, Zheng L, Bosch RJ, et al; AIDS Clinical Trials Group A5244 Team. The effect of raltegravir intensification on low-level residual viremia in HIV-infected patients on antiretroviral therapy: A randomized controlled trial. PLoS Med. 2010 Aug 10;7(8). pii: e1000321. PMID: 20711481.
- Hatano H, Hayes TL, Dahl V, et al. A randomized, controlled trial of raltegravir intensification in antiretroviral-treated, HIV-infected patients with a suboptimal CD4+ T cell response. J Infect Dis. 2010; [in press].
- Hunt PW, Martin JN, Sinclair E, et al. T cell activation is associated with lower CD4+ T cell gains in human immunodeficiency virus-infected patients with sustained viral suppression during antiretroviral therapy. J Infect Dis. 2003 May 15;187(10):1534-43. PMID: 12721933.
- Brenchley JM, Price DA, Schacker TW, et al. Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nat Med. 2006 Dec;12(12):1365-71. PMID: 17115046.
- Schacker TW, Reilly C, Beilman GJ, et al. Amount of lymphatic tissue fibrosis in HIV infection predicts magnitude of HAART-associated change in peripheral CD4 cell count. AIDS. 2005 Dec 2;19(18):2169-71. PMID: 16284469.
- Estes J, Baker JV, Brenchley JM, et al. Collagen deposition limits immune reconstitution in the gut. J Infect Dis. 2008 Aug 15;198(4):456-64. PMID: 18598193.
- Chun TW, Carruth L, Finzi D, et al. Quantification of latent tissue reservoirs and total body viral load in HIV-1 infection. Nature. 1997 May 8;387(6629):183-8. PMID: 9144289.
- Anton PA, Mitsuyasu RT, Deeks SG, et al. Multiple measures of HIV burden in blood and tissue are correlated with each other but not with clinical parameters in aviremic subjects. AIDS. 2003 Jan 3;17(1):53-63. PMID: 12478069.
- Chun TW, Nickle DC, Justement JS, et al. Persistence of HIV in gut-associated lymphoid tissue despite long-term antiretroviral therapy. J Infect Dis. 2008 Mar 1;197(5):714-20. PMID: 18260759.