The Human Immunodeficiency Virus (HIV), CD4+ T lymphoctyes and AIDS

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Human immunodeficiency virus (HIV) infection results from 1 of 2 similar retroviruses (HIV-1 and HIV-2) that destroy CD4+ T lymphocytes and impair cell-mediated immunity, increasing risk of certain infections and cancers.

This article will examine both strains and explain CD4+ T lymphocytes and AIDS in more detail.

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Initial HIV infection may cause nonspecific febrile illness. Risk of subsequent manifestations—related to immunodeficiency—is proportional to the level of CD4+ lymphocyte depletion. HIV can directly damage the brain, gonads, kidneys, and heart, causing cognitive impairment, hypogonadism, renal insufficiency, and cardiomyopathy.

Manifestations range from asymptomatic carriage to acquired immune deficiency syndrome (AIDS), which is defined by serious opportunistic infections or cancers or a CD4 count of < 200/mcL. HIV infection can be diagnosed by antibody, nucleic acid (HIV RNA), or antigen (p24) testing. Treatment aims to suppress HIV replication by using combinations of 3 or more drugs that inhibit HIV enzymes; treatment can restore immune function in most patients if suppression of replication is sustained.

HIV-1 and HIV-2

HIV-1 causes most HIV infections worldwide, but HIV-2 causes a substantial proportion of infections in parts of West Africa. In some areas of West Africa, both viruses are prevalent and may co-infect patients. HIV-2 appears to be less virulent than HIV-1.

HIV-1 originated in Central Africa in the first half of the 20th century, when a closely related chimpanzee virus first infected humans. Epidemic global spread began in the late 1970s, and AIDS was recognized in 1981.

The World Health Organization (WHO) estimates that in 2017, about 36.9 million people, including 1.8 million children (younger than 15 years), were living with HIV worldwide; of the total, about 25.7 million live in sub-Saharan Africa. About 25% of people living with HIV were undiagnosed. Among people who knew they were infected, 79% were accessing treatment. 

In 2017, about 940,000 people died from AIDS-related illnesses worldwide (70% in sub-Saharan Africa), compared to 1.9 million in 2004 and 1.4 million in 2010. In 2017, about 1.8 million people, including 180,000 children, were newly infected with HIV, compared to 3.4 million new infections in 1996. Most new infections (95%) now occur in the developing world; over half are in women in sub-Saharan Africa.

In many sub-Saharan African countries, incidence of HIV infection is declining markedly from the very high rates of a decade before; nevertheless, important gaps remain to meet the World Health Organization’s Fast-Track strategy to end the AIDS epidemic by 2030.

In the United States in 2015, more than 1.1 million people aged over 13 years were estimated to be living with HIV infection; HIV was undiagnosed in about 15% of them. Overall, the number of new cases decreased by 19% from 2005 to 2014. In 2016, 39,782 cases were diagnosed. Over two thirds (67% or 26,570) of new infections occurred in gay and bisexual men. Among gay and bisexual men, the number of new infections was 10,223 in black/African American men, 7,425 in Hispanic/Latino men, and 7,390 in white men.

CD4+ T Lymphocytes

The 2 main types of lymphocytes are

  • B cells (which mature in bone marrow)
  • T cells (which mature in the thymus)

The main types of lymphocytes are morphologically indistinguishable but have different immune functions. They can be distinguished by antigen-specific surface receptors and molecules called clusters of differentiation (CDs), whose presence or absence define some subsets. More than 300 CDs have been identified. Each lymphocyte recognizes a specific antigen via surface receptors.

T cells

T cells develop from bone marrow stem cells that travel to the thymus, where they go through rigorous selection. There are 3 main types of T cell:

  • Helper
  • Regulatory (suppressor)
  • Cytotoxic

In selection, T cells that react to self antigen presented by self MHC molecules or to self MHC molecules (regardless of the antigen presented) are eliminated by apoptosis, limiting the likelihood of autoimmunity. Only T cells that can recognize nonself antigen complexed to self MHC molecules survive; they leave the thymus for peripheral blood and lymphoid tissues.

Most mature T cells express either CD4 or CD8 and have an antigen-binding, Ig-like surface receptor called the T-cell receptor (TCR). There are 2 types of TCR:

  • Alpha-beta TCR: Composed of TCR alpha and beta chains; present on most T cells
  • Gamma-delta TCR: Composed of TCR gamma and delta chains; present on a small population of T cells

Genes that encode the TCR, like Ig genes, are rearranged, resulting in defined specificity and affinity for antigen. Most T cells (those with an alpha-beta TCR) recognize antigen-derived peptide displayed in the MHC molecule of an antigen-presenting cell. Gamma-delta T cells recognize protein antigen directly or recognize lipid antigen displayed by an MHC-like molecule called CD1. As for B cells, the number of T-cell specificities is almost limitless.

For alpha-beta T cells to be activated, the TCR must engage with antigen-MHC. Costimulatory accessory molecules must also interact (eg, CD28 on the T cell interacts with CD80 and CD86 on the antigen-presenting cell); otherwise, the T cell becomes anergic or dies by apoptosis. Some accessory molecules (eg, CTLA-4 [cytotoxic T-lymphocyte antigen 4] on the T cell, which also interacts with CD80 and CD86 on the antigen-presenting cell, PD-1 [programmed cell death protein 1] on the T cell, which interacts with PD-L1 [programmed cell death protein ligand 1] on the antigen-presenting cell) inhibit previously activated T cells and thus dampen the immune response. Molecules such as CTLA-4 and PD-1, and their ligands, are termed checkpoint molecules because they signal that the T cell needs to be restrained from continuing its activity. Cancer cells that express checkpoint molecules may thus be protected from the immune system by restraining the activity of tumor-specific T cells.

Monoclonal antibodies that target checkpoint molecules on either T cells or on tumor cells (termed checkpoint inhibitors) are used to prevent downregulation of antitumor responses and effectively treat some heretofore resistant cancers. However, because checkpoint molecules are also involved in other types of immune response, checkpoint inhibitors can cause severe immune-related inflammatory and autoimmune reactions (both systemic and organ specific).

Polymorphisms in the CTLA-4 gene are associated with certain autoimmune disorders, including Graves disease and type I diabetes.

AIDS

AIDS is defined as one or more of the following:

  • HIV infection that leads to any of certain illnesses highlighted below
  • A CD4+ T lymphocyte (helper cell) count of < 200/mcL
  • A CD4+ cell percentage of ≤ 14%

AIDS-defining illnesses are

  • Serious opportunistic infections
  • Certain cancers (eg, Kaposi sarcoma, non-Hodgkin lymphoma) to which defective cell-mediated immunity predisposes
  • Neurologic dysfunction

AIDS-Defining Illnesses

  • Bacterial infections, multiple or recurrent
  • Candidiasis of bronchi, trachea, or lungs
  • Candidiasis of esophagus
  • Cervical cancer, invasive
  • Coccidioidomycosis, disseminated or extrapulmonary
  • Cryptococcosis, extrapulmonary
  • Cryptosporidiosis, chronic intestinal (lasting > 1 mo)
  • Cytomegalovirus disease (other than liver, spleen, or lymph nodes), onset at age > 1 mo
  • Cytomegalovirus retinitis (with loss of vision)
  • Encephalopathy attributed to HIV
  • Herpes simplex: Chronic ulcers (lasting > 1 mo) or bronchitis, pneumonitis, or esophagitis (onset at age > 1 mo)
  • Histoplasmosis, disseminated or extrapulmonary
  • Isosporiasis (cystoisosporiasis), chronic intestinal (lasting > 1 mo)
  • Kaposi sarcoma
  • Lymphoma, Burkitt (or equivalent term)
  • Lymphoma, immunoblastic (or equivalent term)
  • Lymphoma, primary, of brain
  • Mycobacterium avium complex (MAC) or Mycobacterium kansasii, disseminated or extrapulmonary
  • Mycobacterium tuberculosis of any site, pulmonary, disseminated, or extrapulmonary
  • Mycobacterium, other species or unidentified species, disseminated or extrapulmonary
  • Pneumocystis jirovecii (previously known as Pneumocystis carinii) pneumonia
  • Pneumonia, recurrent
  • Progressive multifocal leukoencephalopathy
  • Salmonella septicemia (nontyphoid), recurrent
  • Toxoplasmosis of brain, onset at age > 1 mo
  • Wasting syndrome attributed to HIV

The Infection Process

HIV attaches to and penetrates host T cells via CD4+ molecules and chemokine receptors. After attachment, HIV RNA and several HIV-encoded enzymes are released into the host cell.

Viral replication requires that reverse transcriptase (an RNA-dependent DNA polymerase) copy HIV RNA, producing proviral DNA; this copying mechanism is prone to errors, resulting in frequent mutations and thus new HIV genotypes. These mutations facilitate the generation of HIV that can resist control by the host’s immune system and by antiretroviral drugs.

Proviral DNA enters the host cell’s nucleus and is integrated into the host DNA in a process that involves integrase, another HIV enzyme. With each cell division, the integrated proviral DNA is duplicated along with the host DNA. Subsequently, the proviral HIV DNA can be transcribed to HIV RNA and translated to HIV proteins, such as the envelope glycoproteins 41 and 120. These HIV proteins are assembled into HIV virions at the host cell inner membrane and budded from the cell surface within an envelop of modified human cell membrane. Each host cell may produce thousands of virions.

After budding, protease, another HIV enzyme, cleaves viral proteins, converting the immature virion into a mature, infectious virion.

Infected CD4+ lymphocytes produce > 98% of plasma HIV virions. A subset of infected CD4+ lymphocytes constitutes a reservoir of HIV that can reactivate (eg, if antiviral treatment is stopped).

Virions have a plasma half-life of about 6 hours. In moderate to heavy HIV infection, about 108 to 109 virions are created and removed daily. The high volume of HIV replication and high frequency of transcription errors by HIV reverse transcriptase result in many mutations, increasing the chance of producing strains resistant to host immunity and drugs.

Immune system

Two main consequences of HIV infection are

  • Damage to the immune system, specifically depletion of CD4+ lymphocytes
  • Immune activation

CD4+ lymphocytes are involved in cell-mediated and, to a lesser extent, humoral immunity. CD4+ depletion may result from the following:

  • Direct cytotoxic effects of HIV replication
  • Cell-mediated immune cytotoxicity
  • Thymic damage that impairs lymphocyte production

Infected CD4+ lymphocytes have a half-life of about 2 days, which is much shorter than that of uninfected CD4+ cells. Rates of CD4+ lymphocyte destruction correlate with plasma HIV level. Typically, during the initial or primary infection, HIV levels are highest (> 106 copies/mL), and the CD4 count drops rapidly.

The normal CD4 count is about 750/mcL, and immunity is minimally affected if the count is > 350/mcL. If the count drops below about 200/mcL, loss of cell-mediated immunity allows a variety of opportunistic pathogens to reactivate from latent states and cause clinical disease.

Other tissues

HIV also infects nonlymphoid monocytic cells (eg, dendritic cells in the skin, macrophages, brain microglia) and cells of the brain, genital tract, heart, and kidneys, causing disease in the corresponding organ systems.

HIV strains in several compartments, such as the nervous system (brain and CSF) and genital tract (semen), can be genetically distinct from those in plasma, suggesting that they have been selected by or have adapted to these anatomic compartments. Thus, HIV levels and resistance patterns in these compartments may vary independently from those in plasma.

Disease progression

During the first few weeks of primary infection, there are humoral and cellular immune responses:

  • Humoral: Antibodies to HIV are usually measurable within a few weeks after primary infection; however, antibodies cannot fully control HIV infection because mutated forms of HIV that are not controlled by the patient’s current anti-HIV antibodies are generated.
  • Cellular: Cell-mediated immunity is a more important means of controlling the high levels of viremia (usually over 106 copies/mL) at first. But rapid mutation of viral antigens that are targeted by lymphocyte-mediated cytotoxicity subvert control of HIV in all but a small percentage of patients.

Plasma HIV virion levels, expressed as number of HIV RNA copies/mL, stabilize after about 6 months at a level (set point) that varies widely among patients but averages 30,000 to 100,000/mL (4.2 to 5 log10/mL). The higher this set point, the more quickly the CD4 count decreases to a level that seriously impairs immunity (< 200/mcL) and results in the opportunistic infections and cancers that define AIDS.

Risk and severity of opportunistic infections, AIDS, and AIDS-related cancers are determined by 2 factors:

  • CD4 count
  • Exposure to potentially opportunistic pathogens

Risk of specific opportunistic infections increases below threshold CD4 counts of about 200/mcL for some infections and 50/mcL for others, as in the following:

  • CD4 count < 200/mcL: Increased risk of Pneumocystis jirovecii pneumonia, toxoplasmic encephalitis, and cryptococcal meningitis
  • CD4 count < 50/mcL: Increased risk of cytomegalovirus (CMV) and Mycobacterium avium complex (MAC) infections

For every 3-fold (0.5 log10) increase in plasma HIV RNA in untreated patients, risk of progression to AIDS or death over the next 2 to 3 years increases about 50%.

Without treatment, risk of progression to AIDS is about 1 to 2%/year in the first 2 to 3 years of infection and about 5 to 6%/year thereafter. Eventually, AIDS almost invariably develops in untreated patients.

Transmission

Transmission of HIV requires contact with body fluids—specifically blood, semen, vaginal secretions, breast milk, saliva, or exudates from wounds or skin and mucosal lesions—that contain free HIV virions or infected cells. Transmission is more likely with the high levels of virions that are typical during primary infection, even when such infections are asymptomatic.

Transmission by saliva or droplets produced by coughing or sneezing, although conceivable, is extremely unlikely. HIV is not transmitted by casual nonsexual contact as may occur at work, school, or home.

Transmission is usually

  • Sexual: Direct transmission through sexual intercourse
  • Needle- or instrument-related: Sharing of blood-contaminated needles or exposure to contaminated instruments
  • Maternal: Childbirth or breastfeeding
  • Transfusion- or transplant-related

Sexual transmission of HIV

Sexual practices such as fellatio and cunnilingus appear to be relatively low risk but not absolutely safe. Risk does not increase significantly if semen or vaginal secretions are swallowed. However, open sores in the mouth may increase risk.

The sexual practices with the highest risks are those that cause mucosal trauma, typically intercourse. Anal-receptive intercourse poses the highest risk. Mucous membrane inflammation facilitates HIV transmission; sexually transmitted diseases, such as gonorrhea, chlamydial infection, trichomoniasis, and especially those that cause ulceration (eg, chancroid, herpes, syphilis), increase the risk several-fold. Other practices that cause mucosal trauma include fisting (inserting most or all of the hand into the rectum or vagina) and using sexual toys. When used during intercourse with an HIV-infected partner and/or with multiple concurrent sex partners, these practices increase the risk of HIV transmission.

In heterosexuals, the estimated risk per coital act is about 1/1000; however, risk is increased in the following:

  • Early and advanced stages of HIV infection when HIV concentrations in plasma and genital fluids are higher
  • Younger people
  • People with ulcerative genital diseases

Circumcision seems to reduce the risk of males acquiring HIV infection by about 50% by removing the penile mucosa (underside of foreskin), which is more susceptible to HIV infection than the keratinized, stratified squamous epithelium that covers the rest of the penis.

Recent evidence shows that HIV infected people in whom antiretroviral therapy has reduced their viral load below the current detectable level (virally suppressed) do not sexually transmit the virus to their partners. Undetectable virus equals an untransmittable virus.

Epidemiology

HIV has spread in 2 epidemiologically distinct patterns:

  • Male homosexual intercourse or contact with infected blood (eg, through sharing needles in injection drug users; before effective screening of donors, through transfusions)
  • Heterosexual intercourse (affecting men and women about equally)

In most countries, both patterns occur, but the first pattern usually predominates in developed countries; the second pattern predominates in Africa, South America, and southern Asia.

In areas where heterosexual transmission is dominant, HIV infection follows routes of trade, transportation, and economic migration to cities and spreads secondarily to rural areas. In Africa, particularly southern Africa, the HIV epidemic has killed tens of millions of young adults, creating millions of orphans. Factors that perpetuate spread include

  • Poverty
  • Poor education
  • Deficient systems of medical care that do not provide access to HIV testing and antiretroviral drugs

However, through international efforts, as of 2016, an estimated 19.5 million people living with HIV were accessing antiretroviral therapy, dramatically reducing deaths and transmission in many countries.

Many opportunistic infections that complicate HIV are reactivations of latent infections. Thus, epidemiologic factors that determine the prevalence of latent infections also influence risk of specific opportunistic infections. In many developing countries, prevalence of latent TB and toxoplasmosis in the general population is higher than that in developed countries. Dramatic increases in reactivated TB and toxoplasmic encephalitis have followed the epidemic of HIV-induced immunosuppression in these countries. Similarly in the United States, incidence of coccidioidomycosis, common in the Southwest, and histoplasmosis, common in the Midwest, has increased because of HIV infection.

Human herpesvirus 8 infection, which causes Kaposi sarcoma, is common among homosexual and bisexual men but uncommon among other HIV patients in the United States and Europe. Thus, in the United States, more than 90% of AIDS patients who have developed Kaposi sarcoma are homosexual or bisexual men.

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