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.
  6. describe the basic treatment regimen (HAART).
  7. 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. 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.

LYMPHOCYTES

OVERVIEW

The organisms, or viruses, discussed in this handout can infect several different cell types, including neurons, epithelial cells, salivary glands, lymphocytes, macrophages, and monocytes. The ability of these viruses to infect lymphocytes is discussed according to the dramatic effects the viruses have on the immune response.

There are two basic types of human lymphocytes: B lymphocytes and T lymphocytes. When activated, B lymphocytes become plasma cells that produce antibodies. B lymphocytes require two different signals to become plasma cells: They must bind antigen with their surface bound antibody, and they must be exposed to cytokines (interleukin 4 [IL-4] and IL-5) produced by T lymphocytes (T-helper cells). Antibody production to foreign antigens is called the humoral immune response.

There are two types of T lymphocytes: T-helper cells (CD4+ cells) and T-cytotoxic cells (CD8+ cells). When activated, the T-cytotoxic cells can eliminate the host cells that are infected with virus, Mycobacteria, certain intracellular bacteria, fungi, parasites, and tumor cells. The cellular immune response occurs when cells kill other cells. The T-cytotoxic cells require two signals to become activated. They must bind antigen with their T-cell receptor, and they must be exposed to cytokine (interferon g) from T-helper cells.

There are two basic types of T-helper cells: Th1 and Th2. These cells are essential in helping the body mount a humoral and a cellular immune response. Th1 T-helper cells produce gamma interferon to activate the T-cytotoxic cells. Th2 T-helper cells produce IL-4 and IL-5 to activate B lymphocytes. Without T-helper cells, the patient’s adaptive immune systems (i.e., humoral and cellular immune response) become much less effective at eliminating microbial invaders.

The diseases discussed in this handout are acquired immunodeficiency syndrome (AIDS), infectious mononucleosis, and cytomegalovirus (CMV) infections. Human immunodeficiency virus (HIV) causes AIDS, and the AIDS virus infects T-helper lymphocytes. CMV causes several different diseases depending on the host infected. CMV can infect many different cell types (e.g., epithelial cells, T cells, macrophages). The infection is spread through the body and establishes a latent infection in T lymphocytes and macrophages. EBV causes infectious mononucleosis and it infects B lymphocytes.

 

HIV/ACQUIRED IMMUNODEFICIENCY SYNDROME

AIDS is an epidemic that has caused significant morbidity and mortality in most countries worldwide. Destruction of CD4+ T lymphocytes (T-helper lymphocytes) predisposes infected individuals to a wide range of opportunistic infections, tumors, dementia, and death.

Etiology

HIV type 1 (HIV-1; group M, N, and O) and HIV-2 are human retroviruses in the lentivirus subfamily. The most common cause of AIDS is HIV-1.

A third type of the HIV virus was reported in August of 2009 in a woman from Cameroon. This third HIV virus shows no evidence of recombination with the two other HIV viruses and is distinct from the HIV-1 group M, N and O viruses. It is similar to the gorilla simian immunodeficiency virus and a proposed name for it is HIV-1 group P (Plantier JC, et al. 2009. A New Human Immunodeficiency Virus Derived from Gorillas. Nature Medicine 15:871-872).

Manifestations

Untreated HIV infection involves three stages of disease (Figure below) and is ultimately fatal. In many patients, symptoms of HIV infection do not occur until stage 3 of the infection. Stage 1, or primary HIV infection, has an incubation period of 1–3 weeks before symptoms begin (Table L-1). Stage 1 ends with the production of high titers of anti-HIV antibodies at 2–3 months postinfection.

HIV/AIDS Manifestations

Table L-1. Symptoms of Stage 1 (Primary HIV Infection)

  • Patient may have NO symptoms OR they may have any or all of the following:
  • “mononucleosis-like symptoms” (i.e., malaise, pharyngitis, low-grade fever, cervical lymphadenopathy)
  • Myalgia
  • Arthralgia
  • Lymphadenopathy
  • Hepatosplenomegaly
  • Headache
  • Meningitis
  • Encephalitis rash (small pink papules or macules over much of the body)

Stage 2 HIV infection is usually asymptomatic and in most cases lasts for 6 years or longer. Patients produce large amounts of anti-HIV antibody. HIV is detectable in blood, semen, and cervical secretions. If symptoms occur, the patient presents with persistent generalized lymphadenopathy or AIDS-related complex (ARC) (Table L-2).

Table L-2. Symptoms of AIDS-related Complex (ARC)

  • Fever
  • Fatigue
  • Diarrhea
  • Weight loss
  • Night sweats
  • Immunologic abnormalities
  • Dementia
  • Spontaneous neoplasms

Stage 3 is usually a period when symptoms of various opportunistic infections or spontaneous neoplasms begin. The severity and frequency of these infections and neoplasms is directly related to the decline of CD4+ T cells.

Epidemiology

AIDS Prevalence 2006
Click on image for an enlarged view.

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.

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".

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 L-6. 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 L-7 through L-10 contain information needed to determine if an HIV-infected patient has AIDS.

Table L-7. 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 L-8. 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 L-9) and C (see Table L-10) must NOT have occurred.

 

Table L-9. 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 L-10. 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.

Therapy and Prevention

Eradication of HIV infection cannot be achieved with currently available antiretroviral regimens; therefore, lifelong treatment to suppress the virus is necessary. Highly active antiretroviral therapy (HAART), available since 1995, has resulted in durable antiviral responses, however, and 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 a longer lifespan for patients. Six different classes of antiretroviral drugs are available and are listed in Table L-11.

Table L-11. Antiretroviral Drugs Used in HAART*

Class of Antiretroviral Drug

Mechanism of Action

Drug Names

Nucleoside or nucleotide reverse transcriptase inhibitors (NRTIs)

NRTIs inhibit HIV’s reverse transcriptase and can be placed within the viral DNA. When the NRTIs are placed in the viral DNA by the reverse transcriptase, transcription of the viral genes is inhibited. This prevents virus replication and subsequent spread of the viral infection.

Abacavir, emtricitabine (FTC), zidovudine (AZT), didanosine (DDI), zalcitabine (DDC), lamivudine (3TC), tenofovir (disoproxil fumarate), reverset (d4FC), and stavudine (D4T)

Nonnucleoside reverse transcriptase inhibitors (NNRTIs)

These drugs also inhibit reverse transcriptase, which prevents virus multiplication and spread.

Efavirenz (EFV), nevirapine, and delavirdine

Protease inhibitors (PIs)

HIV produces its own protease, which 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 form (viral assembly). The PIs inhibit the retroviral protease from cleaving the viral proteins. These drugs help to slow the spread of the virus to other uninfected cells.

Amprenavir, atazanavir, fosamprenavir, ritonavir, indinavir, nelfinavir (NFV), saquinavir, and tipranavir

Fusion entry inhibitors

A peptide that interferes with the viral gp41 protein and prevents fusion of HIV with the host cell.

Enfuvirtide

CCR5 entry inhibitors

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.

Maraviroc

Integrase inhibitor

This drug inhibits the enzyme that integrates HIV genetic material into the host chromosome.

Raltegravir; raltegravir 400 mg twice daily plus emtricitabine plus tenofovir suggested for treatment naïve HIV patients

*HAART, highly active antiretroviral therapy. Note: This list is likely to be incomplete because new antiretroviral drugs are rapidly being approved.

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 L-12. 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

NRTI with Integrase inhibitor

2 NRTIs + raltegravir  (Emtricitabine + tenofovir + raltegravir)

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.

Table L-13. 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 at 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 1/21/10
©2010 Neal R. Chamberlain, Ph.D., All rights reserved.

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