Up to 30% of human immunodeficiency virus (HIV)-infected patients who are receiving long-term highly active antiretroviral therapy do not exhibit a marked increase in the CD4(+) T cell count, despite achieving complete suppression of the HIV load. These patients are referred to as "immunological nonresponders." When treating immunological nonresponders, the practicing clinician has several questions, including questions about the clinical risk associated with persistent immunodeficiency and about possible approaches to treatment that would provide clinical and immunological benefits. However, tentative answers to these questions require investigations of the mechanisms that underlie the lack of immune recovery, because only the deepest comprehension of the immunological gaps underlying functional defects will allow administration of highly targeted and efficacious treatment strategies. The aim of our review is to provide a thorough assessment of the clinical implications of a lack of increase in the CD4(+) T cell count in immunological nonresponders, to examine the immunological gaps limiting recovery of the CD4(+) T cell count, and to note possible therapeutic avenues, which may offer clinicians guidance regarding how to most efficaciously treat these critical patients.

Up to 30% of human immunodeficiency virus (HIV)-infected patients who are receiving long-term highly active antiretroviral therapy do not exhibit a marked increase in the CD4(+) T cell count, despite achieving complete suppression of the HIV load. These patients are referred to as "immunological nonresponders." When treating immunological nonresponders, the practicing clinician has several questions, including questions about the clinical risk associated with persistent immunodeficiency and about possible approaches to treatment that would provide clinical and immunological benefits. However, tentative answers to these questions require investigations of the mechanisms that underlie the lack of immune recovery, because only the deepest comprehension of the immunological gaps underlying functional defects will allow administration of highly targeted and efficacious treatment strategies. The aim of our review is to provide a thorough assessment of the clinical implications of a lack of increase in the CD4(+) T cell count in immunological nonresponders, to examine the immunological gaps limiting recovery of the CD4(+) T cell count, and to note possible therapeutic avenues, which may offer clinicians guidance regarding how to most efficaciously treat these critical patients.