Incomplete Immune Recovery in HIV Infection: Mechanisms, Relevance for Clinical Care, and Possible Solutions

Abstract

<jats:p>Treatment of HIV-infected patients with highly active antiretroviral therapy (HAART) usually results in diminished viral replication, increasing CD4+ cell counts, a reversal of most immunological disturbances, and a reduction in risk of morbidity and mortality. However, approximately 20% of all HIV-infected patients do not achieve optimal immune reconstitution despite suppression of viral replication. These patients are referred to as immunological nonresponders (INRs). INRs present with severely altered immunological functions, including malfunction and diminished production of cells within lymphopoetic tissue, perturbed frequencies of immune regulators such as regulatory T cells and Th17 cells, and increased immune activation, immunosenescence, and apoptosis. Importantly, INRs have an increased risk of morbidity and mortality compared to HIV-infected patients with an optimal immune reconstitution. Additional treatment to HAART that may improve immune reconstitution has been investigated, but results thus far have proved disappointing. The reason for immunological nonresponse is incompletely understood. This paper summarizes the known and unknown factors regarding the incomplete immune reconstitution in HIV infection, including mechanisms, relevance for clinical care, and possible solutions.</jats:p>

Association between discordant immunological response to highly active anti-retroviral therapy, regulatory T cell percentage, immune cell activation and very low-level viraemia in HIV-infected patients

“…In this population of aviraemic patients upon long-term HAART, the immunological discordant response is currently the most relevant clinical outcome and the most frequently encountered problem. Indeed, in iIR, increased mortality has been shown and neurological, cardiovascular and malignant pathologies are most frequently observed [4,6,7].…”

“…Importantly, this incomplete immune recovery, also called inadequate immunological response [4] (iIR), is associated with increased morbidity and mortality [2,3,[5][6][7]. In contrast, patients with a complete immunological response (i.e.…”

“…Many factors have been suspected (reviewed in [4]). Of these, immune cell activation is a hallmark of untreated HIV infection, and a strong prognostic factor of disease severity and progression [8].…”

The future role of CD4 cell count for monitoring antiretroviral therapy

“…50,51 These variabilities in CD4 recovery would not change treatment decisions because there is no evidence for changing ART in those patients with discordance between immunological and virological responses (ie, persistently low CD4 counts despite virological suppression), although there would be a benefi t to continue prophylaxis in such patients. 52 A growing consensus is that monitoring of CD4 count adds little additional value to viral load monitoring once patients are stable on ART with viral suppression. Guidelines issued by the Southern African HIV Clinicians Society recommend that for patients being monitored with viral loads, once the CD4 count is greater than 200 cells per μL and viral load is suppressed (ie, two consecutive undetectable viral loads), there is no need to continue CD4 testing, although CD4 testing is recommended if virological or clinical failure occurs.…”

Frequency of TLR4 (1063A/G and 1363C/T) polymorphisms in healthy and HIV-infected Omani individuals and their relationship to viral load and T cell count

“…The main elements of the pathogenesis induced by human immunodeficiency virus (HIV) infection are the depletion of CD4 T cells and the level of the viral load (VL) (Février et al, 2011), but these elements vary between patients (Gaardbo et al, 2012). The presence of single nucleotide polymorphisms (SNPs) is one of the genetic variations that has been shown to be closely related to the variability of these elements (Dean et al, 1996;Liu et al, 1996;Samson et al, 1996;Bleiber et al, 2005).…”