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Expert Commentary

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)

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.

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.


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