All arboviruses are transmitted by arthropods (arthropodborne) such as mosquitoes and ticks from the wild animal reservoir to humans.

FLAVIVIRUS

Transmission – For effective transmission to occur, the virus must be present in the bloodstream of the vertebrate host (viremia) in sufficiently high titer to be taken up in the small volume of blood ingested during an insect bite. After ingestion, the virus replicates in the gut of the arthropod and then spreads to other organs, including the salivary glands. Only the female of the species serves as the vector of the virus, because only she requires a blood meal in order for progeny to be produced. An obligatory length of time, called the extrinsic incubation period,  must pass before the virus has replicated sufficiently for the saliva of the vector to contain enough virus to transmit an infectious dose.

For most viruses, the extrinsic incubation period ranges from 7 to 14 days.

Clinical Findings – (1) encephalitis; (2) hemorrhagic fever or (3) fever with myalgias, arthralgias, and nonhemorrhagic rash. Immunity is usually lifelong

Yellow Fever Virus

Member of the flavivirus family. Causes yellow fever in the tropical areas of Africa and South America. “Jungle” yellow fever is transmitted from monkeys to humans by mosquitoes.

“Urban” yellow fever is transmitted from human to human by Aedes mosquitoes (i.e., humans are the reservoir in the urban form). Humans are not a “dead-end” host because viremia is high.

 

Dengue Virus

Member of the flavivirus family.

Transmission – by Aedes mosquitoes from one human to another. A monkey reservoir is suspected.

Second episodes may result in dengue hemorrhagic fever, a life-threatening complication.

The pathogenesis is as follows: The patient recovers from classic dengue caused by one of the four serotypes, and antibody against that serotype is produced. When the patient is infected with another serotype of dengue virus, an anamnestic, heterotypic response occurs, and large amounts of cross-reacting antibody to the first serotype are produced. There are two hypotheses about what happens next. One is that immune complexes composed of virus and antibody are formed that activate complement, causing increased vascular permeability and thrombocytopenia. The other is that the antibodies increase the entry of virus into monocytes and macrophages, with the consequent liberation of a large amount of cytokines. In either scenario, shock and hemorrhage result.

HUMAN IMMUNODEFICIENCY VIRUS    

Characteristics—Enveloped virus with two copies (diploid) of a single-stranded, positive-polarity RNA genome. RNAdependent DNA polymerase (reverse transcriptase) makes a DNA copy of the genome, which integrates into host cell DNA. Precursor polypeptides must be cleaved by virus encoded protease to produce functional viral proteins. The tat gene encodes a protein that activates viral transcription. Antigenicity of the gp120 protein changes rapidly; therefore, there are many serotypes.

HIV preferentially infects and kills helper (CD4) T lymphocytes, resulting in the loss of cell-mediated immunity and a high probability that the host will develop opportunistic infections.

There are several important antigens of HIV:

(1) gp120 and gp41 are the type-specific envelope glycoproteins. gp120 protrudes from the surface and interacts with the CD4 receptor (and a second protein, a chemokine receptor) on the cell surface. gp41 is embedded in the envelope and mediates the fusion of the viral envelope with the cell membrane at the time of infection. The gene that encodes gp120 mutates rapidly, resulting in many antigenic variants.

(2) The group-specific antigen, p24, is located in the core and is not known to vary. Antibodies against p24 do not neutralize HIV infectivity but serve as important serologic markers of infection.

Summary of Replicative Cycle

• Entry of HIV into the cell is the binding of the virion gp120 envelope protein to the CD4 protein on the cell surface. The virion gp120 protein then interacts with a second protein on the cell surface, one of the chemokine receptors.
• Next, the virion gp41 protein mediates fusion of the viral envelope with the cell membrane, and the virion core containing the nucleocapsid, RNA genome, reverse transcriptase, protease and intergrase enzyme enters the cytoplasm.
• Chemokine receptors, such as CXCR4 and CCR5 proteins, are required for the entry of HIV into CD4-positive cells.
• Mutations in the gene encoding CCR5 endow the individual with protection from infection with HIV. People who are homozygotes are completely resistant to infection, and heterozygotes progress to disease more slowly.
• In the cytoplasm, reverse transcriptase transcribes the genome RNA into double-stranded DNA, which migrates to the nucleus, where it integrates into the host cell DNA.
• The viral DNA can integrate at different sites in the host cell DNA, and multiple copies of viral DNA can integrate.
• Integration is mediated by a virus-encoded endonuclease (integrase).
• Viral mRNA is transcribed from the proviral DNA by host cell RNA polymerase (augmented by virus encoded Tat protein) and translated into several large polyproteins.
• The Gag and Pol polyproteins are cleaved by the viral protease, whereas the Env polyprotein is cleaved by a cellular protease.
• The Gag polyprotein is cleaved to form the main core protein (p24), the matrix protein (p17), and several smaller proteins. The Pol polyprotein is cleaved to form the reverse transcriptase, integrase, and protease.
• Cleavage by the viral protease occurs as the immature virion buds from the cell membrane.
• It is this cleavage process that results in the mature, infectious virion.

Note that HIV replication is dependent on cell proteins as well as viral proteins. First there are the cell proteins required during the early events, namely CD4, and the chemokine receptors, CCR5 and CXCR4. Cell proteins, such as actin and tubulin, are involved with the movement of viral DNA into the nucleus. The cell protein cyclin T1 and the viral protein Tat are part of the complex that transcribes viral mRNA. Cell proteins are also involved in the budding process by which the virus exits the cell.

 

Pathogenesis—

HIV is first found in the blood 4 to 11 days after infection.

Two receptors are required for HIV to enter cells. One receptor is CD4 protein found primarily on helper T cells. HIV infects and kills helper T cells, which predisposes to opportunistic infections. Other cells bearing CD4 proteins on the surface (e.g., astrocytes) are infected also. The other receptor for HIV is a chemokine receptor such as CCR5. The NEF protein is an important virulence factor. It reduces class I MHC protein synthesis, thereby reducing the ability of cytotoxic T cells to kill HIV-infected cells.

The main immune response to HIV infection consists of cytotoxic CD8-positive lymphocytes. These cells respond to the initial infection and control it for many years. It is the ultimate failure of these cytotoxic T cells that results in the clinical picture of AIDS. Cytotoxic T cells lose their effectiveness because so many CD4 helper T cells have died; thus the supply of lymphokines, such as IL-2, required to activate the cytotoxic T cells is no longer sufficient.

HIV has three main mechanisms by which it evades the immune system: (1) integration of viral DNA into host cell DNA, resulting in a persistent infection; (2) a high rate of mutation of the env gene; and (3) the production of the Tat and Nef proteins that downregulate class I MHC proteins required for cytotoxic T cells to recognize and kill HIVinfected cells. The ability of HIV to infect and kill CD4- positive helper T cells further enhances its capacity to avoid destruction by the immune system.