Unlike most infections in past epidemics, AIDS is distinguished by a very long latent period before the development of any visible signs of infection. During this phase, there is little or no viral replication detectable in peripheral blood mononuclear cells and little or no culturable virus in peripheral blood. The CD4 lymphocyte count remains moderately decreased. However, the immune response to HIV is insufficient to prevent continued viral replication within lymphoid tissues. Tests for HIV antibody will remain positive during this time but p24 antigen tests are usually negative. There is no evidence to suggest that seroreversion, or loss of antibody, occurs in HIV infected persons.
The average HIV-infected person may have an initial acute self-limited illness, may take up to several weeks to become seropositive, and then may live up to 8 or 10 years, on average, before development of the clinical signs and symptoms of AIDS. Persons infected with HIV cannot be recognized by appearance alone, are not prompted to seek medical attention, and are often unaware that they may be spreading the infection. There has been no study to date that shows a failure of HIV-infected persons to evolve to clinical AIDS over time, though the speed at which this evolution occurs may vary.
At least 10% of persons infected with HIV-1 are "long survivors" who have not had significant progressive decline in immune function. Findings include: a stable CD4 lymphocyte count, negative plasma cultures for HIV-1, a strong HIV-1 neutralizing antibody response, and a strong virus-inhibitory CD8 lymphocyte response. In addition, the lymph node architecture is maintained without either the hyperplasia or lymphocyte depletion common to progression to AIDS. Though peripheral blood mononuclear cells contain detectable HIV-1 and viral replication continues in long survivors, though their viral burden is low.
The development of signs and symptoms of AIDS typically parallels laboratory testing for CD4 lymphocytes. A decrease in the total CD4 count below 500/microliter presages the development of clinical AIDS, and a drop below 200/microliter not only defines AIDS, but also indicates a high probability for the development of AIDS-related opportunistic infections and/or neoplasms. Plasma HIV-1 RNA increases as plasma viremia becomes more marked. The risk for death from HIV infection above the 200/microliter CD4 level is low.
There is loss of normal lymph node architecture as the immune system fails with emergence from latency of HIV infection. It is marked by development of generalized lymphadenopathy. This condition, described by the term persistent generalized lymphadenopathy (PGL), is not life-threatening. Lymph nodes throughout the body are large but usually do not exceed 3 cm in size and they may vary in size over time.
Another phase of HIV infection described clinically but no longer commonly diagnosed in practice, is the condition known as AIDS-related complex (ARC), which is not necessarily preceded by PGL. ARC lacks only the opportunistic infections and neoplasms which define AIDS. ARC patients usually show symptoms of fatigue, weight loss, and night sweats, along with superficial fungal infections of the mouth (oral thrush) and fingernails and toenails (onychomycosis). It is uncommon for HIV infected persons to die at the stage of ARC. The staging of HIV disease progression through the use of CD4 lymphocyte counts has made use of the terms PGL and ARC obsolete.
The stage of clinical AIDS that is reached years after initial infection is marked by the appearance of one or more of the typical opportunistic infections or neoplasms diagnostic of AIDS by definitional criteria. The progression to clinical AIDS is also marked by the appearance of syncytia-forming (SI) variants of HIV in about half of HIV infected patients. These SI viral variants, derived from non-syncytia-forming (NSI) variants, have greater CD4 cell tropism and are associated with more rapid CD4+ cell decline. The SI variants typically arise in association with a peripheral blood CD4 lymphocyte count between 400 and 500/microliter, prior to the onset of clinical AIDS. However, appearance of the SI phenotype of HIV is a marker for progression to AIDS that is independent of CD4 cell counts.
Other laboratory findings which indicate progression to AIDS include HIV p24 antigen positivity, increased serum beta2-microglobulin, elevated serum IgA, or increased neopterin levels in serum, cerebrospinal fluid, or urine. The p24 antigen is a highly specific predictor of progression, but only about 60% of HIV-infected persons develop p24 antigenemia prior to onset of clinical AIDS. Beta2-microglobulin is increased with lymphocyte activation or destruction associated with HIV disease progression. Neopterin, as measured in serum or urine, is also a measure of immune system activation and can predict HIV disease progression. The information provided by these tests is similar, so no advantage accrues from performing all of them simultaneously.
For perinatally acquired HIV infection, the time to development of clinical AIDS may be shorter than in adults. Signs associated with HIV infection appear in over 80% of seropositive infants by the age of 5 months. Infants in whom such signs appear at 3 months tend to have decreased survival. About half of children with perinatally acquired HIV infection are alive at 9 years.