Human Immunodeficiency Virus 1 (HIV-1)

HIV-1 disease progression

The clinical course of untreated HIV infection proceeds through four stages. The different clinical stages of HIV infection reflect patient immunological status and virological status. These two surrogate markers are currently widely used in HIV medicine to monitor progression of the infection.

The immunological status is determined by the absolute (cells/ml) or relative (% lymphocytes) number of CD4+ T-cell count.

The virological status is guided by the number of HIV RNA viral load expressed as copies/ml.

The progression of the disease is influenced by several factors, such as co-infection with hepatitis B virus (HBV), hepatitis C virus (HCV) and tuberculosis (TB), viral genetic makeup, and genetic makeup of the host.

Acquisition In approximately 80% of cases, productive infection is the result of infection with only a single virus or single virus-infected cell.

Early infection Recent HIV Infection (RHI) or Primary HIV Infection (PHI). During first 2 days local dissemination of virus takes place: transmission to lamina propria (loose connective tissue which lies beneath the epithelium and together with the epithelium constitutes the mucosa) via dendritic cells, CD4+ T cells, macrophages, and Langerhans cells. Full and partial activation of CD4+ T lymphocytes occurs. Some activated CD4+ T are differentiated into resting CD4+ T memory lymphocytes thus forming a reservoir of HIV infection. On third day of infection HIV-1 carrying and infected cells track to draining lymph nodes from where during the following weeks viral dissemination to distant body sites like brain, spleen, gut associated lymphoid tissue, lymph nodes, and genitourinary tract occurs. Viral spread to the gut-associated lymphoid tissue (GALT) results in increased infection of CD4+ memory effector cells and their rapid depletion. With loss of CD4+ cells in the gut, a considerable translocation of bacteria occurs across this barrier. It was also shown that lung CD4+ T cells are almost entirely lost by 21st day of infection. Thus, this period is characterized by massive depletion of CD4+ cells in organs, which does not affect CD4+ cell counts in peripheral blood. Between 2 to 3 weeks after infection, a mutational shift occurs in viral envelope (Env), which alters the viral co-receptor preference from CCR5 to CXCR4 expanding the target cell repertoir of the virus and making it capable of infecting macrophages in lymphoid tissues. Infection of the thymus occurs in the face of high CD4+ T cell regeneration requirements, resulting in thymic involution that worsens with age leading to drastic decrease in its T-cell renewal capacity.

Acute infection Also known as Primary HIV Infection (PHI) and Acute Retroviral Syndrome (ARS). The period is characterized by massive uncontrolled HIV replication in blood, all lymphoid tissues and particularly mucosal sites, resulting in high levels of free HIV virions circulating in the plasma (millions copies/ml). Peak plasma viral load coincides with the virus entering the central nervious system (CNS) as early as 7-21 days after infection. Rapid depletion of CD4+ T-cells (lymphopenia) can in some cases lead to transient AIDS-defining illnesses in some patients during this stage. About 10% of patients experience flu-like symptoms, which collectively known as AIDS-related complex, can include fever, inflamed lymph nodes, sore throat, and rash. The duration of the acute phase of infection is uncertain and likely varies from one person to the next. On average, detectable plasma viremia first appears about 7 days postinfection, reaches peak concentration 7 to 10 days later, and then decreases to a steady-state, "set point" level within 8 weeks of viral acquisition The stage may last from 4 weeks to up to 6 months.

Seroconversion Also called window period. The period during which a newly infected person develops antibodies to HIV. These antibodies are then detectable by second- and third-generation enzyme immunoassays (EIAs). This period varies from person to person and depends on tests that were used for detection and clade of the virus. Seroconversion may occur anywhere from days to weeks or months following HIV acquisition. Mean window period is about 115-181 days after infection, which means that 50% of all infected persons develop enough antibodies to be detected by modern tests before this time and the rest 50% - after this time. By 6 months after infection, all infected persons are seroconverted. Before seroconversion occurs, HIV-1 infection can be detected by HIV-1 RNA tests which are very sensitive for PHI but false-positive results occur. Results that indicate <5000 copies/ml are considered indeterminate and require re-testing.

Latency period An asymptomatic period of ongoing viral replication and immune destruction. As the brief period of acute HIV-1 infection wanes, the immune system is faced with two problems, both caused by the viremia and both pertaining to CD4+ T cells. The first is to reconstitute depleted memory CD4+ T cell pool in the face of age-attenuated thymic output and peripheral expansion irrespective of ongoing viral replication. The second problem is that the viral replication, in its turn, aggravates those renewal limitations by further impairing lymphopoietic sources (thymus and lymph nodes), and inducing chronic CD4+ T cell activation that drives the virus propagation and kills the cells placing additional strain on maintenance of the "resting" naive and memory CD4+ T cell pools. Eventual development of HIV-specific immune responses as well as the rapidly diminishing availability of activated CD4+ T cell substrates leads to a rapid fall in HIV-1 load after acute infection. This quasi-stable steady state often takes months to become established, usually preceded by a period of strong viral load fluctuations. Gradually, the plasma viral load decreases to the range of 20,000-60,000 copies/ml and remains more or less steady at a concentration that is known as the viral set point. As a rule, the higher the vial set point, the faster infection's progress. A large study found that patients with viral set points greater than 100,000 copies/ml were 10 times more likely to progress to AIDS within 5 years than those with lower viral set points. The level of the HIV viral set point depends on many factors, including viral pathogenicity and the patients' innate immune status and genetic makeup. After the establishment of viral set point, a limited period of stability between HIV replication and the body's immune response to the virus develops. Because their CD4+ T-cell count remains stable and within the normal range, patients feel relatively well during this period. This stage of infection lasts on average between 8 and 10 years. During this time, the virus undergoes an evolution. In order to infect the target cell the virus requires attachment to CD4 receptors that are expressed on the surface of the cellular membrane. It is now known that HIV also needs a chemokine co-receptor adjacent to the CD4 receptor. Two types of chemokine co-receptors are used by HIV: CCR5 (a b-chemokine receptor) and CXCR4 (an a-chemokine receptor). Early in HIV infection, the virus is a nonsyncytial- inducing variant with tropism towards CCR5 receptors (R5-tropic). Non-syncytial-inducing viruses do not induce fusion of T cells (syncytium formation) in vitro. They grow relatively slowly, and grow equally well in monocytes and lymphocytes. At later stages of infection, the virus switches to a syncytial-inducing variant with tropism towards CXCR4 receptors (X4-tropic). Syncytial-inducing viruses grow more rapidly in vitro than nonsyncytial- inducing viruses. Their emergence presages the imminent decay of CD4+ T cells and rapid progress of the disease to AIDS. In any infected patient, there are swarms of viruses with different tropism towards the two different chemokine co-receptors.

Late infection This stage occurs when the host's immune system is immunocompromised to such a degree that without an initiation of Highly Active Anti-Retroviral Therapy (HAART) the infection is going to progress to Acquired Immunodeficiency Syndrome (AIDS) at rapid pace.

Acquired

Immunodeficiency

Syndrome (AIDS) AIDS is characterized by the death of CD4+ cells, which leaves the body vulnerable to life-threatening conditions, such as opportunistic infections and cancers. AIDS occurs in individuals that do not receive HAART (Highly Active ANti-Retroviral Therapy) or in case of Immunologic Failure (when HAART regimen failed). According to the Centers for Disease Control's (CDC) 1993 standards, an HIV-infected individual has AIDS when either (a) their CD4+ cells fall to fourteen percent or less of total lymphocytes, or (b) when the CD4+ count is less than 200 cells/μl or (c) when at least one of a specific set of opportunistic infections or neoplasms occurs (Centers for Disease Control and Prevention 1992). When the absolute CD4þ T-cell count falls to <200 cells/ml, patients become susceptible to opportunistic infections and certain neoplasms each of which is defined as AIDS-Defining Condition. The 26 conditions include:

AIDS dementia complex

Candida of the esophagus, trachea, bronchi and lungs

Coccidiodomycosis

Cryptosporidiosis

Cytomegalovirus infection (excluding liver, spleen, lymph nodes)

Herpes simplex virus (HSV) lasting more than 1 month, or esophageal HSV

Histoplasmosis

Invasive cervical carcinoma

Isospora beli

Kaposi's sarcoma

Lymphoma: Burkitt's, immunoblastic, primary CNS

Mycobacterial infection

Pnemocystis jiroveci

Pneumonia: recurrent within 12 months

Progressive multifocal leukoencephalopathy

Salmonella sepsis

Toxoplasmosis of the brain

Wasting syndrome

Infection

suppressed

with HAART Current HIV treatment guidelines suggest starting combination antiretroviral therapy (cART) only in patients with advanced disease as defined by specific criteria that are revised on an annual basis. HIV replication is measured by quantifying the viral load, defined as the number of viral RNA copies per milliliter of blood plasma. Patients who maintain good adherence to cART often achieve reduction of the viral load to undetectable levels, curbing the destruction of CD4+ T lymphocytes, but not eradicating the virus which reemerges in nearly all patients when cART is stopped. As these lymphocytes repopulate their numbers, the immune system regains strength. Thus cART frequently results in substantial immune reconstitution in HIV-infected individuals. After start of HAART, the virus in the active CD4+ T cells becomes suppressed in two phases:

Early phase An early rapid phase that occurs after a period of 2-3 months of the start of HAART. The early phase of viral suppression is manifested by significant drop in plasma HIV RNA viral load count.

Stable phase A more gradual delayed phase. However, viral replication in the latently infected lymphocytes and monocytes, and in antigen-presenting cells, takes longer to suppress. It has become apparent that this second viral reservoir becomes nearly fully suppressed after more than 6 months of having plasma HIV RNA viral load of <50 copies/ml.