Lymphoreticular and Hematopoetic Infections
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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.

OVERVIEW
Acquired Immunodeficiency Syndrome (AIDS) is currently a growing, worldwide, fatal, pandemic. Destruction of CD4+ T cells predisposes infected individuals to a wide range of opportunistic infections, tumors, dementia and death. 

ETIOLOGY

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.


Table 1. Prevalence of Living Adults with HIV/AIDS in 2006

Region

Prevalence (% of population infected)

Sub-Saharan Africa

5.9%

Caribbean

1.2 %

Eastern Europe and Central Asia

0.9 %

North America

0.8 %

South and Southeast Asia

0.6 %

Latin America

0.5 %

Oceania

0.4 %

Western and Central Europe

0.3 %

East Asia

0.1 %

Table 2. Number of Persons Living with AIDS in the U.S.

Age (Years)

Estimated # of AIDS Cases in 2006

Cumulative Estimated # of AIDS Cases, Through 2006*

Under 13

38

9,156

Ages 13-14

73

1,078

Ages 15-19

401

5,626

Ages 20-24

1,669

36,225

Ages 25-29

3,423

117,099

Ages 30-34

4,349

197,530

Ages 35-39

6,402

213,573

Ages 40-44

7,298

170,531

Ages 45-49

5,628

107,207

Ages 50-54

3,687

59,907

Ages 55-59

2,071

32,190

Ages 60-64

955

17,303

Ages 65 or older

835

15,074

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

Table 3. Modes of Transmission of Human Immunodeficiency Virus (HIV)

Transmission

Mode of Transmission

Comments

Sexual

  • Anal
  • Vaginal
  • Homosexual
  • Heterosexual

Homosexual routes of transmission occur in male homosexuals and are the most common route of transmission in the U.S.

Heterosexual routes of transmission are the most common routes worldwide and in females in the U.S.

Inoculation in blood

  • Transfusion of blood or blood products
  • Needle sharing among intravenous drug users
  • Needlestick, open wound, and mucous-membrane exposure to health care workers (e.g., dentists, oral surgeons)
  • Tattoo needles

Needle sharing in intravenous drug users is the third most common route of transmission in the U.S.

Perinatal

  • Transplacental (intrauterine transmission)
  • Peripartum transmission (during labor and delivery)
  • Breast milk ingestion in neonates

Peripartum transmission and ingestion of breast milk together are the most common means of transmission to children < 5 years of age


AIDS statistics:

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%.

AIDS Prevalence 2006
Click on image for an enlarged view.

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).


PATHOGENESIS

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".


MANIFESTATIONS
High-risk patients with mononucleosis-like symptoms: Persistent generalized lymphadenopathy syndrome (PGL) multiple enlarged lymph nodes

AIDS-related complex (ARC)

CNS disease (seen in long-term survivors)

DISEASE STAGES

The course of AIDS progresses along a series of defined disease stages or classes and ultimately is fatal.

Stage I: acute viral infection

Stage I ends with the production of high titers of anti-HIV antibodies at 2-3 months, postinfection. Anti-HIV antibodies are usually detectable by ELISA by 3-4 weeks.

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.

DIAGNOSIS

There are no unique signs and symptoms of HIV infection, which makes diagnosis difficult unless laboratory tests are performed (Table L-6). A history of high-risk behaviors and complaints of malaise, generalized lymphadenopathy, fever, or rash may be grounds for serologic testing for HIV infection. HIV antibodies are usually detectable with an ELISA within 3–4 weeks after infection. However, false positives occur, and a second ELISA must be performed; if positive, a Western blot test for HIV is necessary to confirm the diagnosis of HIV infection.

Table 4. Diagnostic Tests Used to Detect HIV Infection

Test

Purpose

ELISA

Initial screening; two different ELISA results must be positive before a confirmatory test is performed

Latex agglutination

Initial screening

Western blot analysis

Confirmatory test

p24 antigen

Early marker of infection (detection of a recent infection)

RT-PCR*

Detection of virus RNA in blood (detection of a recent infection) and to confirm treatment efficacy

CD4:CD8 T-cell ratio

Staging the disease and to confirm treatment efficacy

Isolation and culture of virus

Only available in research laboratories

*RT-PCR, reverse transcriptase polymerase chain reaction.

Detection of HIV in the blood using reverse transcriptase polymerase chain reaction (RT-PCR) is also considered a confirmatory test for HIV infection. RT-PCR can be used to detect HIV RNA in plasma during the first 2–4 weeks of infection when patients may be seronegative and yet are infective.

To determine if a neonate born to a HIV-infected mother is infected with HIV, an ELISA to detect HIV protein p24 is performed. Antibodies from an HIV-infected mother cross the placenta, making diagnosis of neonatal infections using serology impossible. RT-PCR of neonatal plasma can also be used to detect HIV infection in neonates.

HIV-infected patients do not receive a diagnosis of AIDS until they have met the clinical definition of AIDS. The clinical definition for AIDS was developed in 1993 and is useful in treatment decisions and in determining the prognosis of the patient. Tables 5 through 8 contain information needed to determine if an HIV-infected patient has AIDS.

Table 5. The 1993 Revised Classification System for the Diagnosis of HIV Infection and AIDS*

CD4 T-Cell Count

CLINICAL CATEGORIES

(A)

Asymptomatic, Acute (primary) HIV or PGL**

(B)

Symptomatic, Neither Category A nor C Conditions†

(C)

AIDS - indicator Conditions ††

> 500/µL

A1

B1

C1

200–499/µL

A2

B2

C2

< 200/µL

A3

B3

C3

HIV, human immunodeficiency virus; AIDS, acquired immunodeficiency disease.

* All patients who can be classified in the shaded cells of the table have AIDS. Persons with AIDS-indicator conditions (category C; see Table L-10) as well as those with CD4+ T-lymphocyte counts < 200/uL (categories A3 or B3) were reportable as AIDS cases in the United States and territories effective January 1, 1993.

** PGL, persistent generalized lymphadenopathy. See Table L-8 for clinical category A conditions.
† See Table L-9 for clinical category B conditions.
†† See Table L-10 for AIDS indicator conditions.

Table 6. Clinical Category A Conditions for Diagnosis of HIV Infections*

Consists of one or more of the conditions listed below in an adolescent or adult with documented HIV infection (e.g., two positive ELISA results for HIV and a positive Western blot)

  • Acute primary HIV infection
  • Asymptomatic HIV infection
  • Persistent generalized lymphadenopathy
  • Accompanying illness or history of acute HIV infection

*Conditions listed in clinical categories B (see Table 7) and C (see Table 8) must NOT have occurred.

 

Table 7. Clinical Category B Conditions for Diagnosis of HIV Infections*

Symptomatic conditions in an HIV-infected adolescent or adult and that are not included among conditions listed in clinical category C and that meet at least 1 of the following criteria:

  • The conditions are attributed to HIV infection or are indicative of a defect in cell-mediated immunity, or
  • The conditions are considered by physicians to have a clinical course or to require management that is complicated by HIV infections.
  • Category B conditions take precedence over those in category A. For example, someone previously treated for oral or persistent vaginal candidiasis (and who has not developed a category C disease), but who is symptomatic, should be classified in clinical category B.

Examples of conditions in clinical category B include but are not limited to:

  • Bacillary angiomatosis
  • Candidiasis, oropharyngeal (thrush)
  • Candidiasis, vulvovaginal; persistent, frequent or poorly responsive to therapy
  • Cervical dysplasia (moderate or severe)
  • Cervical carcinoma in situ
  • Constitutional symptoms, such as fever (38.5°C) or diarrhea lasting > 1 month
  • Hairy leukoplakia, oral
  • Herpes zoster (shingles), involving at least 2 distinct episodes or > 1 dermatome
  • Idiopathic thrombocytopenia purpura
  • Listeriosis
  • Pelvic inflammatory disease, particularly if complicated by tubo-ovarian abscess
  • Peripheral neuropathy

*Conditions listed in category C (see Table L-10) must not have occurred.

Table 8. Clinical Category C Conditions for Diagnosis of HIV Infections*

Includes the clinical conditions listed in the AIDS surveillance case definition. For classification purposes, once a category C condition has occurred, the person will remain in category C and is considered to be a patient with AIDS.

Category C conditions include:

  • Candidiasis of the trachea, bronchi, or lungs
  • Candidiasis of the esophagus
  • Cervical carcinoma, invasive  
  • Coccidioidomycosis, disseminated or extra pulmonary
  • Cryptococcoses, extra pulmonary
  • Cryptosporidiosis, chronic intestinal (> 1 month duration)
  • Cytomegalovirus (CMV) disease (other than liver, spleen, nodes), CMV retinitis (with loss of vision)
  • Encephalopathy; HIV related
  • Herpes simplex: Chronic ulcer(s) (> 1 month duration) or bronchitis, pneumonitis, or esophagitis
  • Histoplasmosis, disseminated or extra pulmonary
  • Isosporiasis, chronic intestinal (> 1 month duration)
  • Kaposi’s sarcoma
  • Lymphoma, primary brain
  • Lymphoma (immunoblastic or equivalent term)
  • Mycobacterium avium complex or Mycobacterium kansasii, disseminated or extra pulmonary
  • Mycobacterium tuberculosis, any site (pulmonary or extra pulmonary)
  • Mycobacterium, other species or unidentified species disseminated or extra pulmonary
  • Pneumocystis jiroveci (carinii) pneumonia, PCP pneumonia
  • Progressive multifocal leukoencephalopathy
  • Pneumonia, recurrent
  • Salmonella septicemia, recurrent
  • Toxoplasmosis of brain
  • Wasting syndrome due to HIV

*A patient with any one of these conditions is defined as an AIDS patient regardless of CD4 T-cell count.



OPPORTUNISTIC INFECTIONS

Therapy for HIV infection.

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
    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.

Table 10. Treatment to Prevent Transmission of HIV from an HIV-infected Mother to the Fetus or Infant

Time of Zidovudine (ZDV) Administration

Regimen

Antepartum

Oral administration of ZDV to the mother initiated 14–34 weeks’ gestation and continued throughout the pregnancy

Intrapartum

Intravenous administration of ZDV to the mother during labor and until delivery and single dose of nevirapine during labor

Postpartum

A single dose of nevirapine to the newborn after birth and oral administration of ZDV to the newborn for the first 6 weeks of life, beginning 8–12 hours after birth


Send comments and email to Dr. Neal R. Chamberlain,  nchamberlain@atsu.edu
Revised 6/5/09
©2009 Neal R. Chamberlain, Ph.D., All rights reserved.