HIV Infections and AIDS

General Goal: To know the major causes of this disease, how it is transmitted, and understand the basic processes that result in  the progression from HIV infection to AIDS.

Specific Educational Objectives: The student should be able to:

1. recite the most likely causes of HIV/AIDS and how this viral infection is usually acquired in the United States (modes of transmission for females and males are different).

2. describe how the virus attaches to human cells. Also know the human cell receptors that the virus attaches to (hint: M-tropic vs. T-tropic viruses).

3. describe the three different HIV/AIDS disease stages and what happens to the immune system during those disease stages.

4. describe the various means of diagnosing HIV/AIDS and when to use which test. You should also know CDC's definition for AIDS.

5. list the most common opportunistic infections that occur in HIV/AIDS patients.

5. describe the basic treatment regimen (HAART).

6. list ways of preventing HIV infections (hint: how do you prevent congenital infections?)

Lecture: Dr. Neal R. Chamberlain

References: 

1. A wonderful and informative website to visit is from Johns Hopkins Medical Center Called "The Body". Go there you will learn alot!
2. Good article at Webpath on HIV and AIDS.
3. An extensive review of HIV/AIDS vaccines and the basic science findings: NIH-Funded AIDS Vaccine Research: A Critical Review by Gregg Gonsalves. For recent updates on vaccines go to http://www.niaid.nih.gov/daids/vaccine/statuslinks.htm
4. Chen RY, Kilby JM, and Saag MS. Enfuvirtide. 2002 Expert. Opin. Investig. Drugs. Dec;11(12):1837-43.

Human immunodeficiency virus (HIV) types 1 and 2, human retroviruses, lentivirus subfamily. HIV is the  causative agent of AIDS. The most common type is HIV-1 and is the infectious agent that has led to the worldwide AIDS epidemic. HIV-2 infection is less common and less virulent, but results in AIDS as well.

EPIDEMIOLOGY

• HIV-1 infection is found worldwide, and HIV-2 is mainly found in West Africa. Table L-3 lists the prevalence of HIV and AIDS in adults by region of the world.

• Two principal genetic groups of HIV-1, designated M (main) and O (outlier), have currently been identified. Genetic group M is highly prevalent and is further classified into 10 established envelope subtypes, A through J.
• HIV-1 subtype B is found predominately in Europe and in North and South America; HIV-1 subtype C is common seen in sub-Saharan Africa.
• HIV-positive persons are infectious during both asymptomatic and symptomatic stages of infection. 
• In 2004, AIDS was the fifth leading cause of death in persons 35–44 years of age in the United States.
• In 2006, about 56,300 persons were diagnosed with HIV infection in the U.S.
• Homosexual and bisexual men of all races and ethnicities and African American men and women are the groups most affected by HIV. Fifty three percent of all new infections in 2006 occurred in homosexual and bisexual men.
• African Americans, while comprising 13% of the U.S. population, accounted for 45% of the new HIV infections in 2006.
• In the U.S., most persons living with AIDS are aged 30–49 years (Table L-4).

*Includes persons with a diagnosis of AIDS from the beginning of the epidemic through 2006.

• The most common mode of transmission of HIV worldwide is heterosexual contact (Table L-5). HIV is NOT transmitted by casual contact or by touching, hugging, kissing, coughing, sneezing, insect bites, water, food, utensils, toilets, and swimming pools or public baths.

• Of the new HIV infections in 2006 53% were acquired by male to male sexual contact, 31% were acquired by high risk heterosexual contact, and 12% were acquired by injection drug use.
• HIV incidence has been steadily increasing among homosexual and bisexual men since the early 1990s.
• New HIV infections by heterosexual contact and by injection drug use have been decreasing over time.
• In 2006, the most common mode of transmission of HIV in males in the United States was male-to-male sexual contact, whereas the most common mode of transmission in females was heterosexual contact.

About 39.5 million people are infected with HIV/AIDS, worldwide (2006). The highest rates of infection are in sub-Saharan Africa where 22 million are estimated to be infected. The prevalence in adults 15-49 years of age in this region is around 5%.

In the United States, AIDS was the 6th leading cause of death in people 25-44 years of age in 2003. There are 1,406,400 patients living with HIV infection in the U.S. (2006; CDC).

The ability of HIV to infect and destroy CD4-expressing T cells (T-helper cells or T-helper lymphocytes) and macrophages induces immunosuppression in patients with AIDS. When large numbers of T-helper cells are destroyed, the body eventually is unable to mount an immune response to infectious agents and to eliminate tumor cells. The severity of the HIV infection is closely aligned with the reduction in CD4 T cells (T-helper cells) and the increase in HIV virus particles in the blood.

During anal and vaginal intercourse, HIV can bind to both Langerhans and dendritic cells in the epithelium. HIV binds to dendritic cells via a lectin called DC-SIGN (CD209 or C-type lectin receptor). The Langerhans and dendritic cells then transport HIV to the regional lymph nodes or peyer’s patches and infect the CD4 T cells. The likelihood of HIV infection being transmitted during anal or vaginal intercourse is higher if the person exposed to an HIV-contaminated secretion already has a sexually transmitted disease such as syphilis, gonorrhea, and genital herpes, which can produce mucosal ulceration and inflammation.

HIV binds with glycoprotein 120 (gp120) to CD4 T cells in the lymph nodes and uses gp41 to enter the host cells. To infect a CD4 T cell, gp120 must bind to two host cell surface receptors. All HIV viruses must bind to the CD4 host cell receptor to infect the host cells. However, depending on the strain of HIV virus, one of two other host CD4 T-cell receptors, known as CCRF and CXCR4, must be present on the cell to be infected by the virus. 

T cell tropic HIV (T-tropic HIV) requires CD4 and CXCR4 host-cell receptors to infect the host cell. T-tropic viruses are usually transmitted via blood and blood products, and are syncytia-inducing viruses that infect CD4 T cells. Mucosal surface tropic HIV (M-tropic HIV) requires CD4 and CCR5 host-cell receptors to infect the host cell. M-tropic viruses are usually transmitted via sexual contact. They infect macrophages and some CD4 T cells, but are not syncytia-inducing viruses.

If HIV is transmitted via percutaneous injection, it can infect dendritic and monocyte-macrophage lineage cells. The macrophage lineage cells produce CD4, CCR5, and CXCR4, which can be infected by M-tropic and T-tropic HIV viruses. The HIV-infected macrophages and dendritic cells can then transport HIV to the regional lymph nodes through the lymph or the bloodstream. Once in the lymph nodes, HIV infects CD4 T cells.

When HIV reaches the lymph node or Peyer’s patch, it continuously replicates in CD4 T cells. The virus and infected CD4 T cells are released from the nodes into the blood and then are transmitted to other areas of the body (e.g., lymph nodes, brain, and spleen). HIV can destroy CD4 T cells in several different ways, including accumulation of the nonintegrated DNA copies of the viral genome, increased permeability of the plasma membrane, syncytia formation, and induction of apoptosis. The host can produce large numbers of CD4 T cells to replace the cells that are destroyed by HIV. However, without treatment, within 6–10 years the ability of the host to replace these cells slows and the number of CD4 T cells decreases.

CD8 T cells are critical in controlling the progression of HIV disease. However, to become activated and kill HIV-infected cells or release factors that suppress viral replication, CD8 T cells must be activated by CD4 T cells. As the number of CD4 T cell decreases, so does the number of activated CD8 T cells. Virus replication is no longer inhibited, and infected cells are not eliminated. The amount of virus in the blood increases, reaching 5000–10,000 viral particles per milliliter of blood.

As the number of CD4 T cells decreases, the ability of the patient to fight certain infections and eliminate malignant cells also is reduced. CD4 T cells are essential in activation of CD8 T cells. CD8 T cells are important in delayed-type hypersensitivity (DTH) responses, which eliminate viral, fungal, and mycobacterial infections as well as malignant cells. CD4 T cells also regulate antibody production by B cells. The ability to produce antibodies in response to an infection is reduced, making bacterial infections more common. As the number of CD4 T cells decreases, HIV-infected monocytes and microglial cells in the brain die and release neurotoxic substances or chemotactic factors that promote inflammation in the brain.

Reservoirs of HIV infection are established early in macrophages and resting T cells during mucosal infection. A pool of latently infected CD4 T cells develops during the very earliest stages of acute HIV infection. Infected cells are able to persist in the patient’s body for extremely long periods of time, possibly decades.

HIV can cross the epithelial barrier through a process known as transcytosis by M cells (these cells line the intestine). Once past the epithelia, HIV is thought to be picked up by antigen presenting cells (APCs), primarily dendritic cells (DCs). Newer work, however, suggests that HIV directly infects CD4+ T lymphocytes in mucosal associated lymphoid tissue (MALT), establishes a fulminant local infection within a few days, and then spreads quickly throughout the body. Recent data suggest that viral reservoirs are established early during mucosal infection. Preventive vaccines must engender a quick and vigorous mucosal immune response.

gp120: HIV recognizes and binds to the CD4 molecule via viral envelope glycoprotein gp120, and then binds to CXCR4 or CCR-5. A "schematic drawing" of gp120 binding to the receptors. Diagram of virus "life cycle".

• fever
• malaise
• lymphadenopathy
• hepatosplenomegaly
• arthralgias

rash

AIDS-related complex (ARC)

• fever - role for TNF, IL-1
• fatigue
• diarrhea
• weight loss
• night sweats
• immunological abnormalities

• dementia
• spontaneous neoplasms

DISEASE STAGES

Stage I: acute viral infection

• Incubation period of 1-3 weeks
• no symptoms, or any or all of the following "mononucleosis-like symptoms":
• fever, headache
• sore throat
• malaise - myalgia, arthralgia
• lymphadenopathy
• hepatosplenomegaly
• meningitis,
• encephalitis rash - small pink papules or macules over much of the body

Stage II: completely asymptomatic

Lasts for 6 or more years in 65-85% of cases.

Patients produce large amounts anti-HIV antibody

HIV is detectable in blood, semen, and cervical secretions.

New PCR procedures show that as many as 1 in 10 peripheral CD4+ cells are infected.

HIV-antibody-complement complexes are trapped in lymph nodes, tonsils, spleen, etc. by follicular dendritic cells (FDC).

CD4+ T cells disappear from the blood because they are sequestered in the lymph nodes (numbers are 5-10X higher than in the peripheral blood)

Follicular Dendritic Cells (FDC) facilitate HIV transmission to uninfected T cells.

When peripheral CD4+ cells number 500-200/µl, the FDC are dying and the internal structure of the lymph node is breaks down; HIV spills over into the blood.

Stage III: overt disease

Severity is directly related to the decline of CD4+ T cells, which causes diminished function by TC, B cells (hypogammaglobinemia), macrophages and NK cells, and leads to opportunistic infections and spontaneous neoplasms.

The individual has a chronic lifelong infection.

Skin. Among the earliest observed AIDS-related conditions occur as infectious or noninfectious skin eruptions.

Fungal infections: Mucosal candidiasis and Thrush (white, non-adherent plaques and erythema)

Intertriginous cutaneous candidiasis

Paronychia Dermatophytosis - Tineas: pedis, cruris, corporis; due to Trichophyton rubrum;

Onychomycosis Disseminated fungal infections showing early skin lesions

Cryptococcus neoformans - meningitis

Histoplasma capsulatum - in endemic areas; pulmonary and renal failure

Sporothrix schenckii -

Viral infections: Herpes simplex non-healing ulcers; genital, perioral, perianal; perform the Tzanck test

Varicella zoster reactivation within the dorsal root ganglion

Molluscum contagiosum (pox virus agent) - umbilicated, skin-colored papules on the face or trunk, confused with acne, sebaceous hyperplasia, disseminated cryptococcosis, and basal-cell carcinoma.

Warts - pre-existing skin and genital warts become difficult to treat

Oral hairy leukoplakia - whitish, corrugated or hairy, adherent plaques, lateral margins of the tongue

Cytomegalovirus - nonhealing perianal or anal ulcers

Bacterial infections: Staphylococcus, Streptococcus, Haemophilus, Pseudomonas: folliculitis, impetigo, cellulitis

Syphilis - rapidly progressing to tertiary syphilis; secondary syphilis may be seronegative; test individuals showing a papulosquamous rash with RPR and/or a silver stain of a skin biopsy

Mycobacterium tuberculosis and avium-intracellulare skin lesions at the site of injections

Noninfectious inflammatory diseases: Seborrheic dermatitis - most common cutaneous manifestation; 3% of the general pop., 85% of the HIV+ pop.; often associated with Malassezia furfur

Psoriasis - exacerbation of existing conditions

Other inflammatory dermatitis - scabies, atopic dermatitis

Malignant neoplasms of the skin: Kaposi's sarcoma - pink to red to purple to brown, anywhere on skin; (1984) HHV8 also called Kaposi's sarcoma herpes virus (KSHV) has a causal role; treatment may not affect survival

Lymphoma - Hodgkin's, non-Hodgkin's, Burkett, etc

Invasive cervical cancer

Other cutaneous manifestations: Epithelioid angiomatosis - violaceous papules and nodules resembling Kaposi's sarcoma

Hair changes - greying, hairline recession

Yellow nail syndrome

Lungs: May have multiple infections.

Pneumocystis carinii: pneumocystosis - damaged alveoli with cyst production.

This airborne fungus is often acquired in childhood as evidenced by specific antibody. Latent infections are reactivated in adults with a severe T-cell deficiency or in children with a moderate T-cell deficiency. Shortness of breath, fever, weight-loss, dry non-productive cough, interstitial infiltrate in both lungs. P. carinii is identified by its characteristic morphology with a Giemsa stain of an induced sputum sample or a sample from a bronchial alveolar lavage; culture of this organism is difficult.

Cytomegalovirus: interstitial pneumonia

Cryptococcus neoformans pneumonia

Pulmonary tuberculosis

Recurrent pneumonia

Gastrointestinal tract.

Oral, anal, and esophageal inflammation

Herpes simplex virus;

Candida albicans: oral thrush and esophagitis;

Epstein-Barr virus: oral hairy leukoplakia

Severe diarrhea and malabsorption of food

Cryptosporidium (another picture of Cypto. and a fecal smear: acid fast stained)

Cytomegalovirus;

Isosporabelli

Mycobacterium avium and M. intracellulare

Lymph nodes. Lymphadenopathy or lymphadenitis

Cryptococcus

Mycobacterium spp.

Kaposi's sarcoma

Eyes. Retinitis and blindness cytomegalovirus

Brain. Toxoplasma gondii: toxoplasmosis Cryptococcus neoformans: chronic meningitis

Eradication of HIV infection cannot be achieved with currently available antiretroviral regimens therefore treatment to suppress the virus is lifelong. This is because a pool of latently infected CD4+ T cells during the very earliest stages of acute HIV infection persists with an extremely long half-life, even with prolonged suppression of plasma viremia to < 50 copies/mL. Treatment has resulted in substantial reductions in HIV-related morbidity and mortality. 

The primary goals of antiretroviral therapy are:

1. maximal and durable suppression of viral load,
2. restoration and/or preservation of immunologic function,
3. improvement of quality of life,
4. reduction of HIV-related morbidity and mortality. 

HAART (Highly Active Antiretroviral Therapy)- therapy, available since 1995, has resulted in durable antiviral responses that are being observed in an increasing number of patients. Many benefits of long term therapy are being reported. Successful HAART results in suppression of viral replication and halts damage to the immune system. It also partially restores the immune system leading to partial restoration of immune function. Clinical benefits accompanying these immunologic benefits include fewer opportunistic infections and longer life for the patients.

Conclusion: The amount of virus in the blood stream is significantly lowered and lowered for long periods of time in patients treated with all three drugs.

With the increased use of PI's the number of deaths due to AIDS can be dramatically reduced.

Classes of anti-retroviral drugs:

1. Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTI's)

NRTIs were the first group of antiretriviral drug approved for use in HIV/AIDS patients. NRTIs inhibit HIV's reverse transcriptase and can be placed within the viral DNA. When the NRTI's are placed in the viral DNA by the reverse transcriptase transcription of the viral genes is inhibited. This prevents virus multiplication and subsequent spread of the viral infection. Nucleosides require phosphorylation before they can affect reverse transcriptase activity. This phosphorylation occurs via host enzymes. The nucleotides are already phosphorylated and do not need to be activated to inhibit the viral enzyme.

2. Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTI's)

These drugs also inhibit reverse transcriptase which prevents virus multiplication and spread. They do it in a slightly different fashion than NRTI's.

3. Protease Inhibitors (PI's)

HIV produces its own protease that is important in the production of infective viral particles. The protease cleaves the viral proteins to the correct sizes so that a mature viral particle can be formed (viral assembly). The protease inhibitors inhibit the retroviral protease from cleaving the viral proteins. These drugs help to slow the spread of the virus to other uninfected cells. Do not use protease inhibitors in monotherapy. HIV quickly becomes resistant to the protease inhibitors.

4. Fusion inhibitors: The drug Enfuvirtide [T-20, pentafuside, Fuzeon (trade name)], is a 36 amino acid peptide that mimics one section of gp41. This peptide inhibits virion-host cell fusion. Gp41 is essential in getting the HIV virion into the host cell. Refer to figure below.

With very few adverse reactions twice a day subcutaneous injections of Enfuvirtide resulted in significant reduction in viral load (about a 1 log reduction) at 24 weeks. This drug was recently (3/03) approved by the FDA for use in patients in the United States. This drug cannot be used alone it must be used with other anti-HIV drugs and is only recommended for patients with HIV-1 virus that is resistant to the other antivirals.

5. CCR5 entry inhibitors (Maraviroc): These inhibitors bind to the CCR5 receptor on the host CD4 cells and block binding of the HIV virion to the surface of the CD4 cells.

The following information was taken from: Antiretroviral Therapy for HIV Infection in 1998; Updated Recommendations of the International AIDS Society-USA Panel.  ("JAMA". Vol. 280, pp. 78-86, Jul. 1, 1998.)

Early treatment of HIV infection has delayed the progression to AIDS. However, certain things should be considered as complicating this picture:

1. virologic response rates to initial therapy with a PI and 2 nucleoside reverse transcriptase inhibitors (nRTIs) range from 60% to 90% and success of initial therapy is less likely as the disease advances;
2. durability of viral suppression beyond 2 years is uncertain; however if viral titers increase studies have shown less opportunitic infections in people who remain on HAART.
3. close drug adherence is essential in preventing viral resistance, and current regimens are difficult;
4. drug interactions resulting from hepatic metabolism of PIs and nonnucleoside reverse transcriptase inhibitors (NNRTIs) increase therapeutic complexity;
5. impact of extended treatment on quality of life is a major consideration; and
6. new and long-term adverse effects are appearing, particularly with PI-containing regimens.

HAART therapy is a complex treatment regimen and requires a strong lifelong commitment from the patient. HAART should be offered to any patient with established HIV infection and a confirmed plasma HIV-1 RNA level of more than 5000–10,000 copies/mL. There are currently three combination regimens employed as initial HAART, which are listed in Table L-12. Plasma viremia is a strong prognostic indicator in HIV infection. The higher the HIV RNA levels in the bloodstream, the worse the patient’s prognosis. Real time PCR is used to determine HIV-1 RNA levels in the blood and is useful in determining a patient’s prognosis and the effectiveness of antiviral treatment.

.

Table 9. HAART Regimens for a Naïve HIV-infected Patient
HAART Regimen	Drugs
NNRTI-based regimens that are PI sparing	1 NNRTI and 2 NRTIs (e.g., efavirenz + zidovudine + lamivudine)
PI-based regimens that are NNRTI sparing	1 or 2 PIs + 2 NRTIs (e.g., lopinavir/ritonavir (co-formulation) + lamivudine + zidovudine )
Triple NRTI regimens that are both PI- and NNRTI-sparing	Abacavir + lamivudine + zidovudine
HAART, highly active antiretroviral therapy; NNRTI, nonnucleoside reverse transcriptase inhibitor; NRTI, nucleoside or nucleotide reverse transcriptase inhibitors; PI, protease inhibitor.

 

Prevention methods that have reduced the incidence of HIV infections include safe-sex practices (condom use), safe use of needles (no needle sharing), and early screening for HIV infection. Circumcised men are less likely to acquire HIV infections than uncircumcised men. Circumcision reduces female-to-male transmission by about 50%; however, circumcision does not appear to prevent HIV transmission in homosexual males. Treatment of HIV-1 infected pregnant women, as indicated below, can prevent most infections of the fetus or infant (Table L-13). There is no vaccine currently available to prevent HIV/AIDS.