What is the role of CD4 cell count in the management of HIV infection?

Updated: Jun 23, 2020
  • Author: Philip A Chan, MD, MS; Chief Editor: John Bartlett, MD  more...
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CD4 cell count

HIV has a particular tropism for cells with the CD4 surface protein, to which it binds with the gp120 envelope glycoprotein. Cells that have CD4 on their surface include macrophages, glial cells in the brain, and T-helper and T-regulatory cells. Macrophages are the site of a long-lived HIV proviral reservoir that makes eradication practically impossible. Loss of glial cells is thought to be related to AIDS-related encephalopathy. [17]

CD4 cells are lost through numerous mechanisms. HIV itself is directly cytotoxic to T cells, but cell death also occurs as part of the natural immune response and cell activation that occurs with any chronic infection. In the case of HIV, however, T-cell replacement from the thymus is adversely affected, so an increased T-cell turnover is not compensated for by a concomitant increase in production.

Long before these mechanisms were fully understood, it was clear that AIDS was characterized by a specific loss of CD4 cells. CD8 cells were relatively spared, leading to a reversal of the usual CD4/CD8 ratio.

As a result of a loss of CD4 cells, several areas of the immune system are affected. Because of a lack of T-cell help, both cellular CD8 responses and humoral antibody responses are less effective. CD8 cytotoxic T cells are less likely to respond to antigens, both ones that had previously produced positive responses and new targets.

B cells, conversely, tend to overproduce IgG, leading to hypergammaglobulinemia, but the specificity of this antibody is poor, and this leads to impairment in antibody-mediated protection overall. Eventually, without treatment, immune dysfunction progresses to the point that life-threatening opportunistic infections (OIs) can occur.

CD4 cells can be readily measured with flow cytometry, using specific antibodies that label CD4 and other T-cell markers such as CD3. Typically, CD4 counts are performed as part of a complete lymphocyte subset analysis, giving both percentages and absolute numbers of CD4 and CD8 cells, B cells, and natural killer (NK) cells. The magnitude of discordance between absolute CD4 cell numbers and CD4 cell percentages is greatest in persons with HIV infection who are co-infected with active hepatitis C virus and have more advanced liver disease. [18]

In adults, the absolute CD4 cell count is the most important. A count below 200 cells/µL is associated with an increase in the relative risk of OIs. [19, 20]

In 1993, the Centers for Disease Control and Prevention (CDC) added a CD4 cell count below 200 cells/µL as a specific surveillance definition of AIDS. Prior to 1993, AIDS could be diagnosed only when an OI occurred in a patient infected with HIV. This change gave a much more accurate representation of people with the highest risk of OIs and death. Early treatment guidelines used this level as the point at which treatment should be initiated, but several observations (and later, formal clinical trials) prompted a shift in the cutoff.

Individuals who wait to start antiretroviral treatment until their CD4 counts are below 350/µL are less likely to have significant improvement in CD4 cell numbers, and they have reduced reconstitution of their immune repertoire (ie, the antigens to which their immune system could respond) and shorter life expectancy. Pretreatment CD4 count may have a prognostic role in predicting risk of death even after the initiation of antiretroviral therapy. [21] Current guidelines recommend immediate initiation of antiretroviral therapy regardless of CD4 cell count. [16, 22, 23, 24, 25, 26, 27, 28]

In children, particularly infants, CD4 cell count and percentages may not accurately reflect the current risk of immune dysfunction. CD4 cell counts and percentages in healthy infants without HIV infection are greater than those in healthy HIV-negative adults. By age 5 years, values decline to those of an adult. Current pediatric guidelines recommend the use of absolute CD4 cell count for monitoring immune status and disease progression in children. [15, 29, 30]

CD4 cell counts decline over time in untreated individuals and may naturally vary from time to time. Measuring CD4 cell counts is important at diagnosis and periodically, as it provides information about immune function. The CD4 cell count guides clinicians in determining the need for prophylactic therapy for OIs. It is recommended that CD4 cell counts be monitored at initiation of therapy, three months after therapy has started, and then every 3-12 months, depending on clinical status. Once a patient is stable on treatment and has suppressed HIV viral load, frequent CD4 cell count monitoring is unnecessary. Current guidelines suggest that CD4 cell counts should be performed annually (or optionally) in patients who have been on antiretroviral therapy for at least two years, have undetectable viral loads, and have CD4 cell counts of 500/µL or more. In general, HIV viral load testing provides a better measure of resistance and noncompliance with treatment. [16, 31, 32]

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