Elucidating the elite: mechanisms of control in HIV-1 infection

In patients with progressive disease, untreated HIV-1 infection is characterized by high viral loads and decreasing CD4⁺T cell counts which lead to opportunistic infection and other AIDS-defining illness. A rare subset of patients termed ‘elite controllers’ (ECs) maintain control over viremia and often retain normal CD4⁺T cell levels without treatment with antiretroviral drugs. For the most part these patients are infected with replication-competent, fit virus. Factors such as strong, polyfunctional cytotoxic T lymphocyte (CTL) responses and retention of T cell proliferative ability appear to be important in control of HIV-1. Defining what enables ECs to control viral replication will aid in the development of effective vaccine and treatment regimens. This review will discuss differences between ECs and progressors while emphasizing recent findings on the immunological response of ECs to HIV-1.

Introduction

During the acute phase of HIV-1 infection, patients experience flu-like symptoms as viral loads peak and CD4⁺T cell counts decline. Within a few weeks, CD4⁺T cell counts partially (but significantly) rebound and viremia decreases to a steady state known as the ‘set point’; this phase of infection is the chronic phase, and typically lasts for several years during which patients are generally asymptomatic (Figure 1). Over time, however, the viral load will begin to increase, and CD4⁺T cell counts decrease if therapy is not initiated. This will be complicated by the detrimental effects of chronic immune activation and microbial translocation.

Highly active anti-retroviral therapy (HAART) is usually a ‘cocktail’ of three antiretroviral drugs. HAART is the current standard of care. HIV-1 has a typical retroviral lifecycle beginning with fusion of the virus to the target cell, reverse transcription of viral RNA, integration of viral DNA into the host genome, and expression of viral proteins by host machinery. Protease then cleaves the Gag polypeptide and, once the maturation process has completed, virions form and bud from the surface of the infected cell. The drugs that constitute HAART regimens target nearly every stage of the viral lifecycle (Table 1) and HAART is believed to completely inhibit ongoing viral replication. This therapy can prevent disease progression, but it cannot cure HIV-1 due, at least in part, to the presence of quiescent, latently infected, resting memory CD4⁺T cells. Activation of these cells results in the expression of HIV-1 genes and release of infectious virions which may then infect other cells [1]. Current treatment guidelines suggest initiation of HAART if CD4⁺T cell levels drop to <350 cells/μL. There is increasing evidence that earlier initiation of HAART results in a survival advantage and may be beneficial with respect to controlling the damaging chronic immune activation that accompanies HIV-1 infection. However, this evidence must be balanced with knowledge of the often deleterious side effects of current HAART regimens.

Some individuals infected with HIV-1 appear to control the virus naturally. A subset of these patients termed ‘long-term non-progressors’ (LTNPs) vary greatly in their levels of viremia, but maintain stable CD4⁺T cell counts. Less than 1% of HIV-1-infected individuals, however, maintain viral loads of <50 copies/mL 2, 3, 4. These individuals are termed ‘elite controllers’ (ECs). ECs test positive for HIV-1 infection with the standard ELISA and western blot diagnostic assays, but usually have extremely low rates of disease progression 5, 6 Sedaghat et al, in press].

Researchers are attempting to elucidate how ECs control replication-competent HIV-1 isolates. One difficulty with studying HIV-1 is the lack of an appropriate small animal model. This mires differences between ECs and progressors in cause-and-effect debates which are difficult to decide definitively. Differences between ECs and progressors may be a result of high levels of viremia in controllers, not a cause. This should be considered when evaluating data, particularly those originating from human subjects where optimal experimental conditions are not possible. Comparisons between ECs and HAART-treated patients help clarify cause-and-effect issues because these patient cohorts exhibit similarly low viral loads but have achieved these levels in different ways 7, 8, 9, but such comparisons may not account for irreversible alterations caused by viremia in progressors. Despite these potential impediments, studying differences between patient cohorts is one of the most important tools at our disposal, and has yielded a great deal of insight into what comprises an effective host response to HIV-1. This review will highlight key differences between ECs and progressors, and will summarize recent findings in the immunological response of ECs to HIV-1 (Table 2).