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Understanding Immune Recovery

February 2000


Since the 1998 International Conference on AIDS in Geneva, researchers have asserted that successful treatment with highly active antiretroviral therapy (HAART) promotes immune reconstitution.

A recent study published in the Journal of Infectious Diseases helps explain the extent of immune reconstitution and the factors determining its outcome after two years of successful HAART.

Without Treatment

Untreated HIV infection causes progressive immune suppression and chronic immune activation.

These conditions are characterized by multiple phenomena. CD4+ cells decline in number and gradually lose their ability to respond to stimulation by antigens. Naïve CD4+ cells, lymphocytes which have not yet encountered an antigen, and CD8+ cells also decline.

HIV disease progression is also characterized by activation of CD8+ cells. This activation is measured by increased expression of CD38 molecules and human leukocyte antigen on the surface of these cells. An additional measure of progressive immune deterioration is decreased expression of CD28 molecules on CD8+ cells. This decrease is associated with a decreased capacity of these cells to multiply in response to stimulation.

Successful treatment with HAART, defined as strong suppression of HIV RNA viral loads, manifests itself when levels of HIV RNA in the peripheral blood and lymph nodes drop and the number and function of CD4+ cells rise.


The increase in CD4+ cells occurs in three distinct phases.

The first phase occurs during the initial three weeks of HAART. CD4+ memory cells rapidly increase in number. Most of these memory cells apparently redistributed themselves from the lymphoid tissue to the peripheral blood.

Naïve CD4+ cells increase in both the peripheral blood and lymphoid tissue at a slower, progressive rate. After initiation of successful HAART, inflammatory cytokine levels also decrease in the lymphoid tissue, which may be responsible for the immediate, strong immunological improvements.

The second phase of immune reconstitution, until week 72, is characterized by a slower median increase of both memory and naïve CD4+ cells.

The third phase, apparent after week 72, is typified by stabilization of the number of median CD4+ cells and an increase in the percentage of naïve cells.

CD8+ cells increased during the first six weeks of therapy followed by a decrease to baseline values. An initial increase in CD8+ memory cells declined and CD8+ naïve cells increased. The percentage of activated CD8+ cells also declined and the median CD4+/CD8+ ratio increased.

T-cell function also improved, increasing dramatically during the first three weeks of HAART and increasing progressively after that until week 108.

The increase in CD4+ cells between weeks 3 and 72 did not correlate with baseline total CD4+ counts, baseline HIV viral load levels or age. The increase in CD4+ cells did correlate significantly with baseline total CD4+ naïve cell counts.

Also, the increase in naïve cells between weeks 3 and 72 correlated with baseline naïve CD4 cells counts. In fact, the total CD4 cell increase during this period was significantly lower in individuals with lower baseline naïve CD4+ cell counts. And the total increase in CD4+ cells at weeks 72 and 108 correlated with both the baseline total and naïve CD4+ counts.

Results of HAART

This small study, with only 19 participants, shows that even in individuals with advanced HIV disease, immune recovery can continue for as long as two years. The long-term increase in CD4+ cells is primarily caused by a slow, progressive increase in CD4+ naïve cells.

In addition, the amount of thymic tissue present may also predict immune recovery. The thymus is responsible for aiding in the development and maturation of naïve CD4+ cells. HIV infection, as well as age, are thought to have negative effects on the thymus. Thymic function may improve with successful HAART and improve the body's capacity to generate naïve T-cells.

Individuals on HAART who do well suppressing HIV RNA viral loads but who do not have significant increases in CD4+ cell levels may have initiated therapy after significant destruction to the thymus and/or subsets of naïve CD4+ cells had already occurred.

A significant degree of immune reconstitution is possible, and the level of immune function present when therapy begins determine outcome. Optimal effects of HAART will be achieved in individuals who initiate therapy before levels of naïve CD4+ cells are depleted.

This study was made possible through a grant from Abbott Laboratories and Glaxo Wellcome Research and Development.


  • Antigen: Any substance that antagonizes or stimulates the immune system to produce antibodies.

  • Baseline: The initial point in a clinical trial, just before a volunteer starts to receive the experimental treatment.

  • Cytokines: Soluble, hormone-like protein, produced by white blood cells, that acts as a messenger between cells.

  • Peripheral blood mononuclear cell: Cells in the bloodstream with one nucleus. Generally refers to lymphocytes and macrophages.

  • Thymus: Mass of glandular tissue (lymphoid organ) found in the upper chest under the breastbone in humans.

Source: HIV Treatment Information News Service




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